CD74

Summary

CD74 (CD74 molecule, HGNC:1697) is a protein-coding gene on chromosome 5q33.1, encoding HLA class II histocompatibility antigen gamma chain (P04233). Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen….

The protein encoded by this gene associates with class II major histocompatibility complex (MHC) and is an important chaperone that regulates antigen presentation for immune response. It also serves as cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF) which, when bound to the encoded protein, initiates survival pathways and cell proliferation. This protein also interacts with amyloid precursor protein (APP) and suppresses the production of amyloid beta (Abeta). Multiple alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 972 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 63 total
• GTEx eGene: eQTL in 4 tissues, sQTL in 16 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug, 1 via a complex or family; 4 molecules with ChEMBL bioactivity
• Approved drugs acting on a complex or family including it: 1 — Repotrectinib (CD74-ROS1)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.85 (unconstrained)
• MANE Select transcript: NM_001025159
• Interaction hub: 5,325 STRING partners (top 1% of genes corpus-wide)
• Notable: 63 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1697
Approved symbol	CD74
Name	CD74 molecule
Location	5q33.1
Locus type	gene with protein product
Status	Approved
Aliases	CLIP
Ensembl gene	ENSG00000019582
Ensembl biotype	protein_coding
OMIM	142790
Entrez	972

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 26 protein_coding, 6 retained_intron, 5 nonsense_mediated_decay

MANE Select: ENST00000009530

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 5, TSL 3: 1, TSL 4: 2, TSL 5: 2

ENST00000009530, ENST00000353334, ENST00000377795, ENST00000517752, ENST00000517791, ENST00000518797, ENST00000522153, ENST00000522246, ENST00000523208, ENST00000523813, ENST00000523836, ENST00000524315, ENST00000881211, ENST00000881212, ENST00000881213, ENST00000881214, ENST00000881215, ENST00000881216, ENST00000881217, ENST00000881218, ENST00000881219, ENST00000881220, ENST00000881221, ENST00000881222, ENST00000881223, ENST00000949574, ENST00000988147, ENST00000988151, ENST00000988154, ENST00000988156, ENST00000988161, ENST00001048190, ENST00001048192, ENST00001048193, ENST00001048196, ENST00001096946, ENST00001096947

RefSeq mRNA: 5 — MANE Select: NM_001025159 NM_001025158, NM_001025159, NM_001364083, NM_001364084, NM_004355

CCDS: CCDS34276, CCDS47308, CCDS47309

Canonical transcript exons

ENST00000009530 — 9 exons

Exon	Start	End
ENSE00000841201	150404680	150404767
ENSE00002129676	150401639	150402250
ENSE00003494107	150402563	150402625
ENSE00003554133	150403121	150403312
ENSE00003569785	150406259	150406321
ENSE00003578099	150405085	150405180
ENSE00003671108	150407152	150407324
ENSE00003680132	150406881	150406960
ENSE00003929500	150412625	150412910

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 895.3092 / max 39437.5779, expressed in 1300 samples.

Highest expression (Bgee): monocyte, leukocyte, mononuclear cell, granulocyte, vermiform appendix.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CD74 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 4 tissues and its splicing (sQTL) in 16 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

20 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Lung	sqtl	7.5e-10	+0.61	5:150393369:C:T
Nerve Tibial	sqtl	5.3e-08	+0.52	5:150375777:G:T
Skin Sun Exposed Lower leg	sqtl	1.2e-07	+0.51	5:150375777:G:T
Artery Tibial	sqtl	4.0e-07	-0.52	5:150375777:G:T
Skin Not Sun Exposed Suprapubic	sqtl	4.9e-06	-0.52	5:150375777:G:T
Thyroid	sqtl	3.5e-05	+0.45	5:150390125:G:C
Artery Aorta	sqtl	1.1e-04	+0.53	5:150390125:G:C
Adipose Subcutaneous	sqtl	4.0e-04	-0.38	5:150375777:G:T
Minor Salivary Gland	sqtl	3.1e-03	+0.90	5:150375777:G:T
Brain Anterior cingulate cortex BA24	sqtl	3.7e-03	-2.81	5:150646947:T:C
Colon Transverse	sqtl	9.5e-03	+0.43	5:150390125:G:C
Esophagus Mucosa	sqtl	1.0e-02	-0.50	5:150393369:C:T
Esophagus Gastroesophageal Junction	sqtl	1.3e-02	-0.55	5:150400475:AAACTAAAGGATGG:A
Whole Blood	sqtl	2.5e-02	-0.32	5:150375777:G:T
Testis	sqtl	3.1e-02	-1.81	5:151391204:C:T
Esophagus Muscularis	sqtl	3.5e-02	-0.45	5:150390125:G:C
Adrenal Gland	eqtl	3.8e-02	+1.34	5:150253958:G:A
Vagina	eqtl	4.7e-02	+1.47	5:150199333:C:T
Heart Atrial Appendage	eqtl	4.9e-02	+0.74	5:150267620:A:G
Esophagus Muscularis	eqtl	5.0e-02	-0.58	5:149434283:AAGAC:A

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
64243	893.8111	1299
64230	0.4835	225
64229	0.4656	220
64231	0.3828	191
64228	0.1662	96

Top tissues by expression

showing 100 of 308 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.93	gold quality
leukocyte	CL:0000738	99.93	gold quality
mononuclear cell	CL:0000842	99.93	gold quality
granulocyte	CL:0000094	99.92	gold quality
vermiform appendix	UBERON:0001154	99.92	gold quality
spleen	UBERON:0002106	99.92	gold quality
lymph node	UBERON:0000029	99.90	gold quality
gall bladder	UBERON:0002110	99.89	gold quality
right lung	UBERON:0002167	99.89	gold quality
upper lobe of lung	UBERON:0008948	99.88	gold quality
lower lobe of lung	UBERON:0008949	99.88	gold quality
upper lobe of left lung	UBERON:0008952	99.88	gold quality
ileal mucosa	UBERON:0000331	99.87	gold quality
caecum	UBERON:0001153	99.86	gold quality
jejunal mucosa	UBERON:0000399	99.82	gold quality
right coronary artery	UBERON:0001625	99.79	gold quality
metanephros cortex	UBERON:0010533	99.77	gold quality
ileum	UBERON:0002116	99.76	silver quality
small intestine Peyer’s patch	UBERON:0003454	99.76	gold quality
peripheral nervous system	UBERON:0000010	99.74	gold quality
nerve	UBERON:0001021	99.74	gold quality
tibial nerve	UBERON:0001323	99.74	gold quality
duodenum	UBERON:0002114	99.73	gold quality
right uterine tube	UBERON:0001302	99.72	gold quality
trigeminal ganglion	UBERON:0001675	99.72	gold quality
rectum	UBERON:0001052	99.71	gold quality
adult organism	UBERON:0007023	99.71	gold quality
small intestine	UBERON:0002108	99.70	gold quality
nasal cavity epithelium	UBERON:0005384	99.69	gold quality
bone marrow cell	CL:0002092	99.67	gold quality
thymus	UBERON:0002370	99.67	gold quality
colonic epithelium	UBERON:0000397	99.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.65	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.65	gold quality
pylorus	UBERON:0001166	99.64	gold quality
right lobe of thyroid gland	UBERON:0001119	99.63	gold quality
left adrenal gland cortex	UBERON:0035825	99.63	gold quality
peritoneum	UBERON:0002358	99.61	gold quality
trachea	UBERON:0003126	99.61	gold quality
omental fat pad	UBERON:0010414	99.61	gold quality
left lobe of thyroid gland	UBERON:0001120	99.60	gold quality
decidua	UBERON:0002450	99.60	gold quality
apex of heart	UBERON:0002098	99.59	gold quality
descending thoracic aorta	UBERON:0002345	99.59	gold quality
right adrenal gland	UBERON:0001233	99.58	gold quality
left adrenal gland	UBERON:0001234	99.58	gold quality
adrenal cortex	UBERON:0001235	99.58	gold quality
coronary artery	UBERON:0001621	99.58	gold quality
left coronary artery	UBERON:0001626	99.56	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.56	gold quality
superficial temporal artery	UBERON:0001614	99.54	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.53	gold quality
spinal cord	UBERON:0002240	99.52	gold quality
tonsil	UBERON:0002372	99.52	gold quality
dorsal root ganglion	UBERON:0000044	99.51	gold quality
thyroid gland	UBERON:0002046	99.51	gold quality
right adrenal gland cortex	UBERON:0035827	99.51	gold quality
endocervix	UBERON:0000458	99.50	gold quality
inferior vagus X ganglion	UBERON:0005363	99.50	gold quality
left uterine tube	UBERON:0001303	99.47	gold quality
thoracic aorta	UBERON:0001515	99.47	gold quality
minor salivary gland	UBERON:0001830	99.47	gold quality
saliva-secreting gland	UBERON:0001044	99.46	gold quality
ascending aorta	UBERON:0001496	99.46	gold quality
skin of leg	UBERON:0001511	99.45	gold quality
blood	UBERON:0000178	99.44	gold quality
skin of abdomen	UBERON:0001416	99.44	gold quality
adenohypophysis	UBERON:0002196	99.44	gold quality
olfactory bulb	UBERON:0002264	99.43	gold quality
pericardium	UBERON:0002407	99.43	gold quality
nipple	UBERON:0002030	99.40	gold quality
tendon of biceps brachii	UBERON:0008188	99.40	gold quality
bronchial epithelial cell	CL:0002328	99.38	gold quality
body of stomach	UBERON:0001161	99.38	gold quality
mucosa of stomach	UBERON:0001199	99.37	gold quality
adult mammalian kidney	UBERON:0000082	99.36	gold quality
mucosa of transverse colon	UBERON:0004991	99.36	gold quality
body of uterus	UBERON:0009853	99.36	gold quality
bronchus	UBERON:0002185	99.35	gold quality
synovial joint	UBERON:0002217	99.35	gold quality
layer of synovial tissue	UBERON:0007616	99.35	gold quality
epithelium of bronchus	UBERON:0002031	99.34	gold quality
transverse colon	UBERON:0001157	99.33	gold quality
mammary duct	UBERON:0001765	99.33	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.32	gold quality
fundus of stomach	UBERON:0001160	99.31	gold quality
upper leg skin	UBERON:0004262	99.31	gold quality
upper arm skin	UBERON:0004263	99.31	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.31	gold quality
renal medulla	UBERON:0000362	99.30	gold quality
lower esophagus	UBERON:0013473	99.30	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.30	gold quality
zone of skin	UBERON:0000014	99.25	gold quality
aorta	UBERON:0000947	99.25	gold quality
ectocervix	UBERON:0012249	99.25	gold quality
urinary bladder	UBERON:0001255	99.24	gold quality
parotid gland	UBERON:0001831	99.24	gold quality
vena cava	UBERON:0004087	99.23	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.23	gold quality
cardia of stomach	UBERON:0001162	99.21	gold quality

Single-cell (SCXA)

Detected in 91 experiment(s), a significant marker in 75.

Experiment	Marker?	Max mean expression
E-CURD-120	yes	77636.53
E-MTAB-8207	yes	49418.44
E-MTAB-8142	yes	45074.94
E-HCAD-15	yes	37451.17
E-CURD-122	yes	33955.64
E-CURD-79	yes	33342.70
E-CURD-89	yes	33230.30
E-MTAB-6678	yes	33205.64
E-MTAB-10042	yes	32506.53
E-CURD-55	yes	29654.84
E-MTAB-6701	yes	29546.18
E-MTAB-9906	yes	28277.82
E-HCAD-24	yes	28209.99
E-GEOD-134144	yes	26741.09
E-GEOD-84465	yes	25925.26

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tonsil	tissue	4925.3	medium
Lymph node	tissue	4694.9	medium
Spleen	tissue	4646.0	medium
Lung	tissue	3692.7	medium
Appendix	tissue	2625.3	high
Small intestine	tissue	2356.5	high
Thymus	tissue	2067.7
Salivary gland	tissue	1946.8	medium
Duodenum	tissue	1762.2	high
Cervix	tissue	1507.1	low
Urinary bladder	tissue	1498.8	medium
Stomach 1	tissue	1460.3	low
Gallbladder	tissue	1431.0	not detected
Fallopian tube	tissue	1131.6	medium
Rectum	tissue	1112.6	low
Liver	tissue	1093.3	not detected
Adipose tissue	tissue	1009.4	not detected
Smooth muscle	tissue	977.0	not detected
Colon	tissue	953.4	low
Bone marrow	tissue	932.3	low
Adrenal gland	tissue	908.2	not detected
Seminal vesicle	tissue	895.5	not detected
Skin 1	tissue	662.1	high
Breast	tissue	654.0	not detected
Spinal cord	tissue	612.3
Choroid plexus	tissue	603.6
Esophagus	tissue	602.6	low
Endometrium 1	tissue	572.8	low
Kidney	tissue	539.4	medium
Heart muscle	tissue	495.2	not detected
Epididymis	tissue	478.8	not detected
Vagina	tissue	448.0	not detected
Pituitary gland	tissue	440.3
Prostate	tissue	432.8	not detected
Locus coeruleus	tissue	396.9
Pancreas	tissue	386.0	not detected
Parathyroid gland	tissue	383.8	not detected
Tongue	tissue	362.2
Thyroid gland	tissue	359.1	low
Ovary	tissue	356.9	low
Hippocampus	tissue	325.9	low
Substantia nigra	tissue	319.3
Medulla oblongata	tissue	308.5
Skeletal muscle	tissue	296.6	not detected
Placenta	tissue	296.3	high
Superior colliculi	tissue	232.3
Midbrain	tissue	223.4
Pons	tissue	223.2
Nucleus accumbens	tissue	206.6
Thalamus	tissue	200.1
Testis	tissue	199.0	low
Hypothalamus	tissue	197.2
Periaqueductal gray	tissue	190.7
Corpus callosum	tissue	189.9
Putamen	tissue	113.0
Septum	tissue	112.8
Olfactory bulb	tissue	112.2
Hippocampal formation	tissue	107.5
Postcentral gyrus	tissue	85.7
Basal ganglia	tissue	84.5	low

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Lateral funiculus (white matter) (1390.1), Blood vessel (1149.1), Nucleus raphe pallidus (1001.4), Nucleus gracilis (913.2), Peritrigeminal nucleus (841.1).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
CCL2	Activation

Upstream regulators (CollecTRI, top): AHR, AP1, AR, ASCL3, ATF1, ATF2, ATF6B, CEBPA, CEBPB, CEBPD, CEBPG, CREB1, CREB3, CREB3L2, CTCF, DLX5, DNMT3B, E2F1, E2F5, EGR1, ESR1, ESRRA, ETS1, EZH2, FOS, FOXP3, FUBP1, GATA1, GATA2, GLI3, GTF2I, HAND1, HBP1, HIF1A, HIVEP1, HNF4A, HNF4G, HOXB1, HR, ID2

miRNA regulators (miRDB)

Targeting CD74 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 40 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-5087	98.01	69.09	965

Functional genomics

gnomAD constraint: pLI 0.000819, LOEUF 0.849, missense Z 0.951 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000009530 — one region, missense o/e 0.87.

Literature-anchored findings (GeneRIF, showing 40)

• Coordinate expression of Ii/CD74 and MHC class II antigens was identified in most fetal tissues (PMID:11897800)
• its cytoplasmic tail regulates endosome fusion and morphology (PMID:12058053)
• MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade (PMID:12782713)
• CD74 represents a novel and promising target for treatment of multiple myeloma. (PMID:15475450)
• Downregulation of HLA-DG is associated with early intrahepatic recurrence of hepatocellular carcinoma (PMID:15688398)
• H.pylori binds to CD74 on gastric epithelial cells & stimulates interleukin-8 production; binding of H. pylori to CD74 presents a novel insight into an interaction of H. pylori with the gastric epithelium leading to upregulation of inflammatory responses (PMID:15845476)
• CD74 is expressed on the surface of gastric cells, and Helicobacter pylori can use this receptor as a point of attachment to gastric epithelial cells, which lead to IL-8 production. (PMID:15972644)
• We demonstrate that CD74-ICD translocates to the nucleus and induces the activation of the p65 member of NF-kappaB in this compartment. (PMID:16107560)
• H. pylori urease B binds to CD74 on gastric epithelial cells and initiates NF-kappaB activation and interleukin-8 production. (PMID:16428763)
• Residues favoring AP3 binding introduced into a protein that is transported via the PM such as the invariant chain can re-route such protein into direct sorting to late endosomal/lysosomal structures. (PMID:16542748)
• link the disruption of transmembrane helix interactions to previously reported losses of invariant chain function (PMID:16618111)
• Ii can also be detected in the class I MHC peptide loading complex. (PMID:16678175)
• Prostate cancer cell lines had increased MIF gene expression and protein levels; cell growth and invasion required MIF activated signal transduction pathways that were not necessary for growth or viability of androgen-dependent prostate cells (PMID:17142775)
• analysis of interaction between a secreted hookworm Macrophage Migration Inhibitory Factor (MIF) and the human MIF receptor CD74 (PMID:17567581)
• The cytoplasmic region of Vpu was found to interact with the 30-amino-acid cytoplasmic tail of CD74. (PMID:17959659)
• These findings identify Ii and lipid rafts as key regulators of CD1a organization on the surface of immature DCs and of its immunological function as Ag-presenting molecule (PMID:18178838)
• This study provides several lines of evidence to demonstrate the complex interactions of major histocompatibility (MHC) class II invariant chain (Ii) with neonatal Fc receptor for IgG (FcRn). (PMID:18684948)
• The observations indicate that CD74 and the AGTR1 become associated in the early biosynthetic pathway, and that CD74 is a negative regulator of AGTR1 expression. (PMID:18719072)
• Expression of Ii by breast tumor cells may quantitatively and qualitatively alter the presentation of antigens on those cells. (PMID:18828016)
• CD74 acts as a receptor for MIF in podocytes and may play a role in the pathogenesis of diabetic nephropathy (PMID:18842989)
• Increased expression of CD74 can enhance kidney cancer cell proliferation, anchorage independence, invasion, and tumor cell-induced human umbilical vein endothelial cell migration in vitro as well as tumor growth and metastasis in vivo. (PMID:18941249)
• We found intense CD74 expression by immunohistochemistry in 57 of 70 human specimens of non-small cell lung cancer (PMID:19131591)
• CD74 levels are increased in plaques and PBMC from patients with carotid stenosis and are associated with intima-medial thickness in subjects free from clinical cardiovascular diseases. (PMID:19423618)
• at late stages of Vaccinia virus infection, reductions in cellular invariant chain levels coupled with changes in lysosomal protease activity, contribute in part to defects in class II presentation (PMID:19592662)
• Data show that CD74 forms functional complexes with CXCR4 that mediate MIF-specific signaling. (PMID:19665027)
• CD74 activation inhibits in a dose-dependent manner up to 90% of in vitro migration of MSCs, with consistent effects observed among multiple MSC donor preparations. (PMID:20198449)
• CD74 and its target gene transcripts (TA)p63 and very late antigen (VLA)-4 facilitate migration of chronic lymphocytic leukemia cells back to the bone marrow (BM), where they interact with the supportive BM environment that rescues them from apoptosis. (PMID:20357260)
• CD74 is expressed in a subset of high grade gliomas and may contribute to temozolomide resistance (PMID:20443131)
• Overexpression of MIF and CD74 in the placenta may up-regulate the CRP level in maternal blood, which may be involved in the pathogenesis of preeclampsia. (PMID:20646540)
• Simultaneous inhibition of TAP and Ii completely down-modulated the expression of HLA-DR, demonstrating that together these molecules form the key mediators of HLA class II antigen presentation in leukemic blasts. (PMID:20820776)
• These findings are supportive of a role for CD74 in the development and maintenance of gastrointestinal neoplasia. (PMID:21228923)
• Studies indicate that in chronic lymphocytic leukemia cells, binding of MIF to CD74 induces nuclear factor-kappaB activation and up-regulation of TAp63 expression, resulting in the secretion of interleukin 8, which in turn promotes cell survival. (PMID:21417823)
• Synergistic TLR agonist stimulation in combination with IFN-alpha and IFN-gamma was the best method for regulating CD38 and CD74 expression (PMID:21423200)
• CatG was found to be dispensable in invariant chain conversion within intact primary human B cells and dendritic cells. (PMID:21543057)
• These results suggest that cancer cells in the PNI areas could acquired a growth advantage that could be triggered by the growth factor receptors EGFR and CD74. (PMID:21748758)
• overexpression of MIF and CD74 in cervical squamous cell carcinomas and its precancerous lesions and upregulation of VEGF secretion in cervical cancer cells indicate MIF and CD74 may play critical roles in pathogenesis and angiogenesis of cervical cancer (PMID:21792010)
• This is the first study reporting that Ii chain up-regulation occurs on naturally infected antigen presenting cells obtained directly from HIV(+) subjects. (PMID:21945129)
• HIV-1 glycoprotein 41 ectodomain induces activation of the CD74 protein-mediated extracellular signal-regulated kinase/mitogen-activated protein kinase pathway to enhance viral infection. (PMID:22039051)
• Data show that FTY720-mediated disruption of the autophagic-lysosomal pathway led to increased levels of CD74, a potential therapeutic target in mantle cell lymphoma (MCL) that is degraded in the lysosomal compartment. (PMID:22042694)
• Class I homozygosity at 5’VNTR is a significant risk factor of T1DM and acts independently from HLA haplotype in determining the actual risk of diabetes in children. (PMID:22069105)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cd74a	ENSDARG00000009087
danio_rerio	cd74b	ENSDARG00000036628
mus_musculus	Cd74	ENSMUSG00000024610
rattus_norvegicus	Cd74	ENSRNOG00000018735

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96534) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 36 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased CD4-positive, alpha-beta T cell number	7
abnormal antigen presentation via MHC class II	5
abnormal level of surface class II molecules	4
abnormal antigen presentation	3
decreased susceptibility to experimental autoimmune encephalomyelitis	3
abnormal dendritic cell antigen presentation	2
defective assembly of class II molecules	2
decreased B cell proliferation	2
decreased T cell proliferation	2
increased neutrophil cell number	1
increased monocyte cell number	1
decreased leukocyte cell number	1
decreased cell proliferation	1
decreased body size	1
arrested B cell differentiation	1
decreased IgM level	1
abnormal B cell differentiation	1
abnormal professional antigen presenting cell physiology	1
abnormal B cell physiology	1
increased myocardial infarct size	1
increased susceptibility to experimental autoimmune encephalomyelitis	1
abnormal positive T cell selection	1
increased eosinophil cell number	1
decreased lymphocyte cell number	1
decreased B cell number	1

+11 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RD69	97.6%	Diamond
Aquarana catesbeiana	P31226	57.1%	Diamond
Actinia equina	P81439	56.1%	Diamond
Hadronyche infensa	A0A1D0C023	47.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ARSI	protein-coding	340075
TCOF1	protein-coding	6949
NDST1-AS1	ncRNA	102546298
RPS14	protein-coding	6208
NDST1	protein-coding	3340

Protein

Protein identifiers

HLA class II histocompatibility antigen gamma chain — P04233 (reviewed: P04233)

Alternative names: HLA-DR antigens-associated invariant chain, Ia antigen-associated invariant chain

All UniProt accessions (4): E7EQJ3, P04233, H0YBZ2, H0YBZ8

UniProt curated annotations — full annotation on UniProt →

Function. Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II takes place. Serves as cell surface receptor for the cytokine MIF. Binds to the peptide-binding site of MHC class II alpha/beta heterodimers forming an alpha-beta-CLIP complex, thereby preventing the loading of antigenic peptides to the MHC class II complex until its release by HLA-DM in the endosome. Stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of antigen-presenting cells (APCs). Has antiviral activity by stymieing the endosomal entry of Ebola virus and coronaviruses, including SARS-CoV-2. Disrupts cathepsin-mediated Ebola virus glycoprotein processing, which prevents viral fusion and entry. This antiviral activity is specific to p41 isoform.

Subunit / interactions. Homotrimer. In the endoplasmic reticulum (ER) it forms a heterononameric MHC II-Ii complex: 3 MHC class II molecules (heterodimers of an alpha and a beta subunit) bind to the CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system, the CD74 component undergoes sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide) attached to the MHC class II molecule (alpha-beta-CLIP complex). This processed complex interacts with HLA_DM and HLA_DO heterodimers in order to release CLIP and facilitate the binding of antigenic peptides to the MHC class II molecules. Interacts with CD44; this complex is essential for the MIF-induced signaling cascade that results in B cell survival. Interacts with the mature form of CTSL; the complex survive in neutral pH environment.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Golgi apparatus. trans-Golgi network. Endosome. Lysosome. Secreted Late endosome.

Tissue specificity. Detected in urine (at protein level). In B cells, represents 10% of total CD74 expression. In B cells, represents 70% of total CD74 expression.

Post-translational modifications. O-glycosylated with core 1 or possibly core 8 glycans. Contains chondroitin sulfate.

Disease relevance. A chromosomal aberration involving CD74 is found in a non-small cell lung tumor. Results in the formation of a CD74-ROS1 chimeric protein.

Domain organisation. Antiviral activity requires delivery of the thyroglobulin domain to the endosomal membrane.

Isoforms (5)

UniProt ID	Names	Canonical?
P04233-1	p45, Long	yes
P04233-2	p35, Short
P04233-3	3
P04233-4	p41
P04233-5	p33

RefSeq proteins (5): NP_001020329, NP_001020330, NP_001351012, NP_001351013, NP_004346 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000716	Thyroglobulin_1	Domain
IPR011988	MHC_II-assoc_invariant_trimer	Domain
IPR015386	MHC_II-assoc_invar/CLIP_MHC-bd	Domain
IPR022339	MHC_II-assoc_invar_chain	Family
IPR036613	MHCII_invariant_trimer_sf	Homologous_superfamily
IPR036857	Thyroglobulin_1_sf	Homologous_superfamily
IPR043530	CD74_antigen	Family
IPR052001	MHC-II_Gamma/Thyroglobulin	Family

Pfam: PF00086, PF08831, PF09307

UniProt features (41 total): helix 8, glycosylation site 6, splice variant 4, strand 4, disulfide bond 3, region of interest 3, topological domain 2, mutagenesis site 2, chain 1, peptide 1, site 1, modified residue 1, sequence conflict 1, transmembrane region 1, turn 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

24 structures by resolution:

PDB	Title	Method	Resolution (Å)
4X5W	HLA-DR1 with CLIP102-120(M107W)	X-RAY DIFFRACTION	1.34
7YX9	MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange	X-RAY DIFFRACTION	1.76
3PDO	Crystal Structure of HLA-DR1 with CLIP102-120	X-RAY DIFFRACTION	1.95
1ICF	CRYSTAL STRUCTURE OF MHC CLASS II ASSOCIATED P41 II FRAGMENT IN COMPLEX WITH CATHEPSIN L	X-RAY DIFFRACTION	2
7YXB	MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange	X-RAY DIFFRACTION	2.1
7Z0Q	MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange	X-RAY DIFFRACTION	2.1
1MUJ	Crystal structure of murine class II MHC I-Ab in complex with a human CLIP peptide	X-RAY DIFFRACTION	2.15
5KSV	Crystal structure of HLA-DQ2.5-CLIP2	X-RAY DIFFRACTION	2.19
4AEN	HLA-DR1 with covalently linked CLIP106-120 in reversed orientation	X-RAY DIFFRACTION	2.2
8VSJ	Engineered peptide-specific binder in complex with HLA-DR1/CLIP	ELECTRON MICROSCOPY	2.28
3QXD	F54C HLA-DR1 bound with CLIP peptide	X-RAY DIFFRACTION	2.3
4AH2	HLA-DR1 with covalently linked CLIP106-120 in canonical orientation	X-RAY DIFFRACTION	2.36
9EJH	Peptide-independent T cell receptor recognition of HLA-DQ2	X-RAY DIFFRACTION	2.45
3PGC	Crystal Structure of HLA-DR1 with CLIP106-120, flipped peptide orientation	X-RAY DIFFRACTION	2.66
3QXA	HLA-DR1 bound with CLIP peptide	X-RAY DIFFRACTION	2.71
3PGD	Crystal Structure of HLA-DR1 with CLIP106-120, canonical peptide orientation	X-RAY DIFFRACTION	2.72
5KSU	Crystal structure of HLA-DQ2.5-CLIP1 at 2.73 resolution	X-RAY DIFFRACTION	2.73
1A6A	THE STRUCTURE OF AN INTERMEDIATE IN CLASS II MHC MATURATION: CLIP BOUND TO HLA-DR3	X-RAY DIFFRACTION	2.75
8VRW	Cryo-EM structure of human invariant chain in complex with HLA-DR15	ELECTRON MICROSCOPY	3.03
8VSP	Cryo-EM structure of human invariant chain in complex with HLA-DQ	ELECTRON MICROSCOPY	3.12
9CYM	Structure of LAG3 bound to the MHC class II molecule I-A(b)	X-RAY DIFFRACTION	3.84
9CYL	Structure of LAG3 loop1 deletion bound to the MHC class II molecule I-A(b)	X-RAY DIFFRACTION	4.66
1IIE	HLA-DR ANTIGENS ASSOCIATED INVARIANT CHAIN	SOLUTION NMR
1L3H	NMR structure of P41icf, a potent inhibitor of human cathepsin L	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04233-F1	70.49	0.26

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 8VSJ

Human Protein Atlas

Protein class: CD markers, Transporters, Predicted membrane proteins, Predicted secreted proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Potential drug targets

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
208–209	breakpoint for translocation to form a cd74-ros1 fusion protein

Post-translational modifications (1)

Type	Positions
Phosphoserine	25

Disulfide bonds (3)

Type	Positions
Disulfide bond	213–232, 243–250, 252–271

Glycosylation sites (6)

Type	Positions
N-linked (glcnac…) asparagine	130, 136, 256
O-linked (galnac…) threonine	203
O-linked (galnac…) serine	281
O-linked (xyl…) (chondroitin sulfate) serine	282

Mutagenesis-validated functional residues (2)

Position	Phenotype
225–226	decreases inhibition of ebola virus infection.
225–226	no effect on inhibition of ebola virus infection.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 9; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-202733	Cell surface interactions at the vascular wall	curated
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells	curated
R-HSA-2132295	MHC class II antigen presentation	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-1266738	Developmental Biology	—
R-HSA-9734767	Developmental Cell Lineages	—
R-HSA-9820448	Developmental Cell Lineages of the Exocrine Pancreas	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—

MSigDB gene sets: 665 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, CREL_01, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_B_CELL_HOMEOSTASIS, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_BY_P53_CLASS_MEDIATOR

GO Biological Process (42): prostaglandin biosynthetic process (GO:0001516), positive regulation of cytokine-mediated signaling pathway (GO:0001961), T cell activation involved in immune response (GO:0002286), positive regulation of dendritic cell antigen processing and presentation (GO:0002606), negative regulation of peptide secretion (GO:0002792), positive regulation of type 2 immune response (GO:0002830), negative regulation of mature B cell apoptotic process (GO:0002906), intracellular protein transport (GO:0006886), positive regulation of gene expression (GO:0010628), immunoglobulin mediated immune response (GO:0016064), antigen processing and presentation (GO:0019882), antigen processing and presentation of endogenous antigen (GO:0019883), negative regulation of cell migration (GO:0030336), positive regulation of B cell proliferation (GO:0030890), positive regulation of prostaglandin biosynthetic process (GO:0031394), positive regulation of chemokine production (GO:0032722), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), response to type II interferon (GO:0034341), macrophage migration inhibitory factor signaling pathway (GO:0035691), regulation of macrophage activation (GO:0043030), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043518), T cell selection (GO:0045058), positive regulation of monocyte differentiation (GO:0045657), host-mediated suppression of symbiont invasion (GO:0046597), positive regulation of fibroblast proliferation (GO:0048146), protein stabilization (GO:0050821), positive regulation of macrophage cytokine production (GO:0060907), protein-containing complex assembly (GO:0065003), protein trimerization (GO:0070206), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of neutrophil chemotaxis (GO:0090023), negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:1902166), positive regulation of chemokine (C-X-C motif) ligand 2 production (GO:2000343), positive regulation of macrophage migration inhibitory factor signaling pathway (GO:2000448), adaptive immune response (GO:0002250), immune system process (GO:0002376), protein folding (GO:0006457), immune response (GO:0006955), positive regulation of MAPK cascade (GO:0043410)

GO Molecular Function (12): amyloid-beta binding (GO:0001540), cytokine receptor activity (GO:0004896), cytokine binding (GO:0019955), MHC class II protein complex binding (GO:0023026), macrophage migration inhibitory factor binding (GO:0035718), MHC class II protein binding (GO:0042289), CD4 receptor binding (GO:0042609), MHC class II protein binding, via antigen binding groove (GO:0042658), identical protein binding (GO:0042802), protein folding chaperone (GO:0044183), nitric-oxide synthase binding (GO:0050998), protein binding (GO:0005515)

GO Cellular Component (29): Golgi membrane (GO:0000139), nucleus (GO:0005634), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), multivesicular body (GO:0005771), vacuole (GO:0005773), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020), transport vesicle membrane (GO:0030658), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), trans-Golgi network membrane (GO:0032588), protein-containing complex (GO:0032991), macrophage migration inhibitory factor receptor complex (GO:0035692), NOS2-CD74 complex (GO:0035693), MHC class II protein complex (GO:0042613), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), lumenal side of endoplasmic reticulum membrane (GO:0098553), extracellular region (GO:0005576), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Hemostasis	1
Adaptive Immune System	1
Developmental Cell Lineages of the Exocrine Pancreas	1
Immune System	1
Developmental Biology	1
Developmental Cell Lineages	1

GO top-level categories

showing 60 of 93 GO namespaces:

Category	Terms
cytokine-mediated signaling pathway	3
positive regulation of cytokine production	3
bounding membrane of organelle	3
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
cytokine binding	2
protein binding	2
cytoplasm	2
cytoplasmic vesicle membrane	2
prostaglandin metabolic process	1
prostanoid biosynthetic process	1
regulation of cytokine-mediated signaling pathway	1
positive regulation of signal transduction	1
positive regulation of response to cytokine stimulus	1
lymphocyte activation involved in immune response	1
immune response	1
T cell activation	1
dendritic cell antigen processing and presentation	1
positive regulation of antigen processing and presentation	1
regulation of dendritic cell antigen processing and presentation	1
peptide secretion	1
regulation of peptide secretion	1
negative regulation of secretion	1
regulation of type 2 immune response	1
type 2 immune response	1
positive regulation of immune response	1
mature B cell apoptotic process	1
negative regulation of B cell apoptotic process	1
regulation of mature B cell apoptotic process	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
B cell mediated immunity	1
immune system process	1
antigen processing and presentation	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
prostaglandin biosynthetic process	1
regulation of prostaglandin biosynthetic process	1
positive regulation of unsaturated fatty acid biosynthetic process	1
chemokine production	1
regulation of chemokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
response to cytokine	1
innate immune response	1
peptide binding	1
transmembrane signaling receptor activity	1
immune receptor activity	1
MHC protein complex binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 38 of 83 annotations. The rest are phylogenetic / computational / electronic (IEA).

38 experimentally-supported GO terms:

GO term	NS	Evidence
host-mediated suppression of symbiont invasion	BP	direct assay
negative regulation of DNA damage response, signal transduction by p53 class mediator	BP	direct assay
negative regulation of apoptotic process	BP	direct assay
negative regulation of cell migration	BP	mutant phenotype
negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	BP	mutant phenotype
negative regulation of peptide secretion	BP	direct assay
positive regulation of B cell proliferation	BP	mutant phenotype
positive regulation of ERK1 and ERK2 cascade	BP	direct assay
positive regulation of canonical NF-kappaB signal transduction	BP	direct assay
positive regulation of chemokine production	BP	mutant phenotype
positive regulation of cytokine-mediated signaling pathway	BP	mutant phenotype
positive regulation of fibroblast proliferation	BP	mutant phenotype
positive regulation of gene expression	BP	mutant phenotype
positive regulation of interleukin-6 production	BP	mutant phenotype
positive regulation of interleukin-8 production	BP	mutant phenotype
positive regulation of macrophage migration inhibitory factor signaling pathway	BP	mutant phenotype
positive regulation of monocyte differentiation	BP	direct assay
positive regulation of prostaglandin biosynthetic process	BP	mutant phenotype
prostaglandin biosynthetic process	BP	direct assay
response to type II interferon	BP	direct assay
Golgi apparatus	CC	direct assay
cell surface	CC	direct assay
cytoplasm	CC	direct assay
extracellular exosome	CC	high-throughput assay
macrophage migration inhibitory factor receptor complex	CC	direct assay
membrane	CC	direct assay
nucleus	CC	direct assay
plasma membrane	CC	direct assay
protein-containing complex	CC	direct assay
vacuole	CC	direct assay
CD4 receptor binding	MF	physical interaction
MHC class II protein binding, via antigen binding groove	MF	direct assay
MHC class II protein complex binding	MF	direct assay
amyloid-beta binding	MF	physical interaction
cytokine binding	MF	physical interaction
cytokine receptor activity	MF	direct assay
macrophage migration inhibitory factor binding	MF	physical interaction
protein folding chaperone	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 5,325 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD74	MIF	P14174	899
CD74	CD44	P16070	769
CD74	CTSS	P25774	758
CD74	DDT	P30046	750
CD74	HLA-DQB2	P05538	748
CD74	HLA-DMA	P28067	703
CD74	HLA-DRA	P01903	701
CD74	CD68	P34810	696
CD74	APP	P05067	676
CD74	TREM2	Q9NZC2	669
CD74	TMEM119	Q4V9L6	664
CD74	CSF1R	P07333	660
CD74	ROS1	P08922	655
CD74	SLC34A2	O95436	654
CD74	CD1D	P15813	654

IntAct

Human interaction partners of CD74 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

19 partners by confidence:

Partner	Interaction type	MIscore	Records
CXCR4	colocalization	0.560	4
HLA-DRA	association	0.560	2
HADHA	physical association	0.550	1
HLA-DQA1	proximity	0.540	2
PGRMC1	association	0.530	1
CXCR2	physical association	0.520	2
EIF3E	physical association	0.500	1
KPNB1	physical association	0.500	1
CD44	colocalization	0.460	9
APP	direct interaction	0.440	1
HSPA1A	direct interaction	0.440	1
HLA-DPA1	physical association	0.400	1
ALG3	physical association	0.370	1
CCR1	physical association	0.370	1
PB1	physical association	0.370	1
ROPN1L	association	0.350	1
TM4SF20	association	0.350	1
DSCR9	physical association	0.000	1
UBA1	ubiquitination reaction	0.000	1

BioGRID (166 interactions; top human partners by supporting records): COPG1 (Affinity Capture-MS; 4 records), COPG2 (Affinity Capture-MS; 4 records), HLA-DPB1 (Affinity Capture-MS; 3 records), TM4SF20 (Affinity Capture-MS; 3 records), EIF3E (Affinity Capture-MS; 2 records), HADHA (Affinity Capture-MS; 2 records), KPNB1 (Affinity Capture-MS; 2 records), MIF (Reconstituted Complex; 2 records), PGRMC1 (Affinity Capture-MS; 2 records), AKAP8 (Affinity Capture-MS), ANKRD28 (Affinity Capture-MS), AP3D1 (Affinity Capture-MS), APP (Reconstituted Complex), ARCN1 (Affinity Capture-MS), ASCC1 (Affinity Capture-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
MIF	up-regulates	CD74	binding
CD74	up-regulates	CXCR4	binding
MIF	“up-regulates activity”	CD74	binding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ AGTR1-CD74 complex	2	CD74, AGTR1

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
APP	receptor	Signaling by Amyloid-beta precursor protein

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neutrophil degranulation	5	7.7×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
immune response	6	16.6×	6e-05

Disease & clinical

Genetic variants

Variant evidence for CD74: 63 ClinVar records (0 pathogenic / likely pathogenic); 3 GWAS associations.

ClinVar

63 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	5
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 555):

Position(s)	Effect	Δscore	Sites
5:150402561–150402562	donor_loss	1.0000	5
5:150403313–150403314	acceptor_loss	1.0000	5
5:150403320	acceptor_gain	1.0000
5:150403327	acceptor_gain	1.0000
5:150405087	donor_gain	1.0000
5:150406258	donor_loss	1.0000	2
5:150406322–150406323	acceptor_loss	1.0000	6
5:150406324	acceptor_gain	1.0000
5:150406879–150406880	donor_loss	1.0000	4
5:150406961–150406962	acceptor_loss	1.0000	5

AlphaMissense

401 missense substitutions predicted likely pathogenic (of 1,962 scored), across 115 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F181	8	0.885	0.965
N165	8	0.851	0.940
C232	7	0.991	0.998
C213	7	0.988	0.998
C243	7	0.983	0.992
C252	7	0.981	0.992
C250	7	0.978	0.986
W251	7	0.972	0.998
F191	7	0.953	0.981
F228	7	0.951	0.986
C271	7	0.947	0.974
W178	7	0.934	0.993
W184	7	0.925	0.983
W188	7	0.920	0.978
Q242	7	0.908	0.987
F254	7	0.898	0.952
D233	7	0.859	0.933
D140	7	0.694	0.799
G257	6	0.963	0.996
G236	6	0.932	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (TCGA)	favorable	9.48e-05

Disease associations

OMIM: gene MIM:142790 | disease phenotypes:

GWAS associations

3 associations:

Study	Trait	p-value
GCST004132_118	Crohn’s disease	2e-19
GCST004131_47	Inflammatory bowel disease	3e-15
GCST003264_465	Post bronchodilator FEV1/FVC ratio	4e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2111430 (PROTEIN-PROTEIN INTERACTION), CHEMBL4680046 (CHIMERIC PROTEIN), CHEMBL4692 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CD74 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
MILATUZUMAB	Antibody	2

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes CD74 — the drug acts on the assembly or class, not necessarily on this subunit alone.

1 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
REPOTRECTINIB	CD74-ROS1	2	4

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 26,054 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

4 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3545311	BRIGATINIB	4	5,988
CHEMBL601719	CRIZOTINIB	4	15,133
CHEMBL3286830	LORLATINIB	4	3,833
CHEMBL4298138	REPOTRECTINIB	4	1,100

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs2748249	platinum	Toxicity	Allele A is associated with increased severity of Drug Toxicity when treated with platinum in people with Carcinoma, Non-Small-Cell Lung as compared to allele C.	PMID:24220096
rs1560661	platinum	Toxicity	Allele C is associated with decreased severity of Drug Toxicity when treated with platinum in people with Carcinoma, Non-Small-Cell Lung as compared to allele T.	PMID:24220096

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
milatuzumab	Binding	9.3	pKd

Binding affinities (BindingDB)

29 measured of 30 human assays (30 total across all organisms); most potent 29 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
AP-26113	IC50	0.37 nM
CHEMBL6165880	IC50	0.9 nM
Lorlatinib	IC50	5.5 nM	US-11517561: Macrocycle and composition comprising thereof
4-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	10 nM
6-chloro-1-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one	IC50	13 nM
6-chloro-4-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	16 nM
1-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-6-chloro-3,4-dihydroquinolin-2(1H)-one	IC50	18 nM
6-chloro-1-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one	IC50	18 nM
1-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one	IC50	23 nM
4-(1-(3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	23 nM
1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol	IC50	30 nM
4-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	32 nM
1-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-6-chloro-3,4-dihydroquinazolin-2(1H)-one	IC50	33 nM
1-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one	IC50	33 nM
Repotrectinib	IC50	39 nM	US-12129258: Diaryl macrocyclic compound and pharmaceutical composition, and use thereof
1-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one	IC50	48 nM
4-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	48 nM
4-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	60 nM
1-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one	IC50	65 nM
4-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one	IC50	68 nM
1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-propan-2-ol	IC50	75 nM
4-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one	IC50	80 nM
1-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one	IC50	88 nM
4-(1-(3-(5-acetyl-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	100 nM
4-(1-(3-(5-acetyl-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)-2-hydroxypropyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	120 nM
4-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	130 nM
5-methyl-4-(1-(3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	145 nM
1-(1-(2-hydroxy-3-(5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)benzo[e][1,4]oxazepin-2(1H,3H,5H)-one	IC50	163 nM
4-(1-(3-(3-(4-bromophenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)propyl)piperidin-4-yl)-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one	IC50	170 nM

ChEMBL bioactivities

46 potent at pChembl≥5 of 52 total, top 45 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.64	IC50	0.23	nM	LORLATINIB
9.52	IC50	0.3	nM	LORLATINIB
9.15	IC50	0.7	nM	REPOTRECTINIB
8.80	IC50	1.6	nM	CHEMBL6165880
8.41	IC50	3.9	nM	CRIZOTINIB
7.88	IC50	13.2	nM	BRIGATINIB
7.75	IC50	18	nM	BRIGATINIB
7.60	IC50	25	nM	CRIZOTINIB
7.10	IC50	80	nM	CHEMBL1256304
7.05	IC50	90	nM	CHEMBL1255976
6.94	IC50	115	nM	CHEMBL1257465
6.39	IC50	410	nM	CHEMBL201461
6.12	IC50	750	nM	CHEMBL408418
6.09	IC50	810	nM	CHEMBL206745
6.05	IC50	900	nM	CHEMBL377511
6.05	IC50	900	nM	CHEMBL1289631
6.03	IC50	930	nM	CHEMBL207003
6.02	IC50	950	nM	CHEMBL204525
6.01	IC50	980	nM	CHEMBL377684
5.96	IC50	1100	nM	CHEMBL205748
5.96	IC50	1100	nM	CHEMBL205919
5.92	IC50	1200	nM	CHEMBL1289632
5.89	IC50	1300	nM	CHEMBL203102
5.89	IC50	1300	nM	CHEMBL239179
5.89	IC50	1300	nM	CHEMBL414587
5.85	IC50	1400	nM	CHEMBL381369
5.85	IC50	1400	nM	CHEMBL208344
5.82	IC50	1500	nM	CHEMBL206035
5.82	IC50	1500	nM	CHEMBL523238
5.80	IC50	1600	nM	CHEMBL380361
5.80	IC50	1600	nM	CHEMBL383835
5.75	IC50	1800	nM	CHEMBL379769
5.75	IC50	1800	nM	CHEMBL406247
5.72	IC50	1900	nM	CHEMBL377683
5.70	IC50	2000	nM	CHEMBL208103
5.70	IC50	2000	nM	CHEMBL379351
5.60	IC50	2500	nM	CHEMBL498412
5.60	IC50	2500	nM	CHEMBL498410
5.58	IC50	2600	nM	CHEMBL380541
5.57	IC50	2700	nM	CHEMBL379770
5.46	IC50	3500	nM	CHEMBL1288977
5.40	IC50	4000	nM	CHEMBL496155
5.36	IC50	4400	nM	CHEMBL206067
5.16	IC50	7000	nM	CHEMBL1257355
5.10	IC50	8000	nM	CHEMBL496373

PubChem BioAssay actives

46 with measured affinity, of 134 total; 42 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Lorlatinib	1680101: Inhibition of CD74-ROS1 (unknown origin) expressed in mouse BaF3 cells assessed as reduction in cell viability	ic50	0.0002	uM
Repotrectinib	2256012: Inhibition of ROS1/CD74 (unknown origin) expressed in mouse BaF3 cells	ic50	0.0007	uM
3-[6-[4-[[4-[1-[4-[[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperidin-4-yl]piperazin-1-yl]methyl]piperidin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione	2256012: Inhibition of ROS1/CD74 (unknown origin) expressed in mouse BaF3 cells	ic50	0.0016	uM
Crizotinib	1680101: Inhibition of CD74-ROS1 (unknown origin) expressed in mouse BaF3 cells assessed as reduction in cell viability	ic50	0.0039	uM
Brigatinib	2256012: Inhibition of ROS1/CD74 (unknown origin) expressed in mouse BaF3 cells	ic50	0.0132	uM
3-[(3-hydroxyphenyl)methyl]-5-methoxy-1,3-benzoxazol-2-one	516522: Inhibition of human recombinant biotinylated MIF/CD74 interaction after 30 mins	ic50	0.0800	uM
3-[(2-methoxyphenyl)methyl]-5-methyl-1,3-benzoxazol-2-one	516522: Inhibition of human recombinant biotinylated MIF/CD74 interaction after 30 mins	ic50	0.0900	uM
3-[(3-methoxyphenyl)methyl]-5,6-dimethyl-1,3-benzoxazol-2-one	516522: Inhibition of human recombinant biotinylated MIF/CD74 interaction after 30 mins	ic50	0.1150	uM
4-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	0.4100	uM
1-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]-6-chloro-3,4-dihydroquinolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	0.7500	uM
4-[1-[3-[5-acetyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	0.8100	uM
4-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]pyrido[3,2-b][1,4]oxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	0.9000	uM
4-[1-[(2,3-dimethoxyphenyl)methyl]triazol-4-yl]phenol	539283: Inhibition of human biotinylated MIF/CD74 interaction	ic50	0.9000	uM
1-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-5H-4,1-benzoxazepin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	0.9300	uM
4-[1-[3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	0.9500	uM
6-chloro-1-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-3,4-dihydroquinolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	0.9800	uM
4-[1-[3-[5-acetyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	1.1000	uM
1-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]-3,4-dihydroquinazolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	1.1000	uM
methyl 3-[[4-(4-hydroxyphenyl)triazol-1-yl]methyl]benzoate	539283: Inhibition of human biotinylated MIF/CD74 interaction	ic50	1.2000	uM
6-chloro-4-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	1.3000	uM
4-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]pyrido[3,2-b][1,4]oxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	1.3000	uM
1-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2lambda6,1,3-benzothiadiazin-1-yl)piperidin-1-yl]-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propan-2-ol	263659: Inhibition of MHC2 invariant chain	ic50	1.3000	uM
1-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-4H-3,1-benzoxazin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	1.4000	uM
1-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-3,4-dihydroquinazolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	1.4000	uM
3-benzyl-5-methyl-1,3-benzoxazol-2-one	410820: Inhibition of human MIF-CD74 binding	ic50	1.5000	uM
1-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]-6-chloro-3,4-dihydroquinazolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	1.5000	uM
4-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-5-methyl-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	1.6000	uM
4-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	1.6000	uM
4-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	1.8000	uM
1-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-3,4-dihydroquinolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	1.8000	uM
6-chloro-1-[1-[2-hydroxy-3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-3,4-dihydroquinazolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	1.9000	uM
1-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]-3,4-dihydroquinolin-2-one	263659: Inhibition of MHC2 invariant chain	ic50	2.0000	uM
5-methyl-4-[1-[3-[5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	2.0000	uM
7-[(3-fluoroanilino)-pyridin-2-ylmethyl]quinolin-8-ol	410820: Inhibition of human MIF-CD74 binding	ic50	2.5000	uM
[2-(1-benzofuran-2-yl)-4-oxo-3,1-benzoxazin-6-yl] acetate	410820: Inhibition of human MIF-CD74 binding	ic50	2.5000	uM
4-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]propyl]piperidin-4-yl]-6-chloro-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	2.6000	uM
1-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2lambda6,1,3-benzothiadiazin-1-yl)piperidin-1-yl]propan-2-ol	263659: Inhibition of MHC2 invariant chain	ic50	2.7000	uM
4-(4-benzyltriazol-1-yl)phenol	539283: Inhibition of human biotinylated MIF/CD74 interaction	ic50	3.5000	uM
1-benzofuran-2-yl(2,3-dihydroindol-1-yl)methanone	410820: Inhibition of human MIF-CD74 binding	ic50	4.0000	uM
4-[1-[3-[3-(4-bromophenyl)-5-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperidin-4-yl]-6-chloro-1,4-benzoxazin-3-one	263659: Inhibition of MHC2 invariant chain	ic50	4.4000	uM
3-[(2,3-dimethoxyphenyl)methyl]-5-methyl-1,3-benzoxazol-2-one	516522: Inhibition of human recombinant biotinylated MIF/CD74 interaction after 30 mins	ic50	7.0000	uM
2-[(E)-2-(4-hydroxyphenyl)ethenyl]quinolin-8-ol	410820: Inhibition of human MIF-CD74 binding	ic50	8.0000	uM

CTD chemical–gene interactions

73 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases reaction, increases expression, decreases expression, increases abundance, affects cotreatment	5
sodium arsenite	affects expression, decreases reaction, increases expression, decreases expression	4
Vehicle Emissions	affects cotreatment, decreases reaction, increases expression	3
trichostatin A	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, increases expression	1
tremortin	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
nobiletin	decreases expression	1
quercitrin	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium tungstate(VI)	increases expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
tamibarotene	increases expression	1
bergamottin	decreases expression	1
N-(3-nitratopivaloyl)cysteine ethyl ester	decreases expression	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1021635	Binding	Inhibition of human MIF-CD74 binding	Discovery of human macrophage migration inhibitory factor (MIF)-CD74 antagonists via virtual screening. — *J Med Chem*

Cellosaurus cell lines

24 cell lines: 23 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1BL	Abcam Raji CD74 KO 1	Cancer cell line	Male
CVCL_B1BM	Abcam Raji CD74 KO 2	Cancer cell line	Male
CVCL_B8D7	Abcam HCT 116 CD74 KO	Cancer cell line	Male
CVCL_B8TQ	Abcam MCF-7 CD74 KO	Cancer cell line	Female
CVCL_B9FE	Abcam A-549 CD74 KO	Cancer cell line	Male
CVCL_C8SZ	CUTO-23	Cancer cell line
CVCL_C8T0	CUTO-33	Cancer cell line	Female
CVCL_C8T1	CUTO-27	Cancer cell line
CVCL_C8T3	CUTO-37	Cancer cell line
CVCL_C8T4	CUTO-38	Cancer cell line

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CD74 across ~30M SureChEMBL compounds — explore on Sugi Predict.