SDC4

Summary

SDC4 (syndecan 4, HGNC:10661) is a protein-coding gene on chromosome 20q13.12, encoding Syndecan-4 (P31431). Cell surface proteoglycan which regulates exosome biogenesis in concert with SDCBP and PDCD6IP.

The protein encoded by this gene is a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling. The encoded protein is found as a homodimer and is a member of the syndecan proteoglycan family. This gene is found on chromosome 20, while a pseudogene has been found on chromosome 22.

Source: NCBI Gene 6385 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 37 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10661
Approved symbol	SDC4
Name	syndecan 4
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	SYND4, amphiglycan, ryudocan
Ensembl gene	ENSG00000124145
Ensembl biotype	protein_coding
OMIM	600017
Entrez	6385

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000372733, ENST00000901705, ENST00000901706, ENST00000939835

RefSeq mRNA: 1 — MANE Select: NM_002999 NM_002999

CCDS: CCDS13350

Canonical transcript exons

ENST00000372733 — 5 exons

Exon	Start	End
ENSE00000844969	45330366	45330564
ENSE00000906918	45335782	45335920
ENSE00001458498	45325288	45327415
ENSE00003469221	45348325	45348424
ENSE00003612880	45333023	45333069

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 166.3356 / max 4088.4798, expressed in 1773 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187435	166.1498	1773
187434	0.1858	59

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	99.03	gold quality
nasal cavity epithelium	UBERON:0005384	98.99	gold quality
cartilage tissue	UBERON:0002418	98.93	gold quality
type B pancreatic cell	CL:0000169	98.62	gold quality
epithelium of bronchus	UBERON:0002031	98.53	gold quality
bronchus	UBERON:0002185	98.48	gold quality
bronchial epithelial cell	CL:0002328	98.47	gold quality
skin of abdomen	UBERON:0001416	98.44	gold quality
nasal cavity mucosa	UBERON:0001826	98.41	gold quality
skin of leg	UBERON:0001511	98.17	gold quality
lateral globus pallidus	UBERON:0002476	98.16	gold quality
adult mammalian kidney	UBERON:0000082	98.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.06	gold quality
nipple	UBERON:0002030	98.02	gold quality
upper leg skin	UBERON:0004262	97.98	gold quality
zone of skin	UBERON:0000014	97.93	gold quality
islet of Langerhans	UBERON:0000006	97.85	gold quality
renal medulla	UBERON:0000362	97.83	gold quality
saphenous vein	UBERON:0007318	97.57	gold quality
right lobe of liver	UBERON:0001114	97.50	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.35	gold quality
upper arm skin	UBERON:0004263	97.34	gold quality
body of stomach	UBERON:0001161	97.32	gold quality
tibial artery	UBERON:0007610	97.23	gold quality
inferior olivary complex	UBERON:0002127	97.21	gold quality
popliteal artery	UBERON:0002250	97.21	gold quality
upper lobe of left lung	UBERON:0008952	97.21	gold quality
upper lobe of lung	UBERON:0008948	97.18	gold quality
liver	UBERON:0002107	97.16	gold quality
minor salivary gland	UBERON:0001830	96.99	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	2476.71
E-MTAB-10855	yes	1841.63
E-HCAD-1	yes	86.49
E-MTAB-6701	yes	79.60
E-MTAB-5061	yes	27.32
E-HCAD-10	yes	18.81
E-MTAB-10553	yes	18.81
E-MTAB-6678	yes	16.72
E-GEOD-84465	yes	13.18
E-GEOD-83139	yes	11.72
E-MTAB-8498	yes	9.94
E-GEOD-130148	yes	9.80
E-HCAD-9	yes	9.30
E-ENAD-27	yes	6.14
E-MTAB-7303	no	311.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARNT, CREB1, F2R, F2RL1, HIF1A, NFKB1, NFKB, POU2F1, REL, RELA, RUNX2, SRY, ZNF384

miRNA regulators (miRDB)

82 targeting SDC4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349

Literature-anchored findings (GeneRIF, showing 40)

• Studies suggest that antithrombin regulates neutrophil migration via effects of its heparin-binding site on cell surface syndecan-4. (PMID:11549250)
• Syndecan-4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and monocytes (PMID:11801740)
• Clustering induces redistribution of syndecan-4 core protein into raft membrane domains (PMID:11889131)
• Syndecan-4 core protein mediates the effects of fibroblast growth factor (FGF)2 on cell function. PKCalpha activation and PDZ-mediated formation of a serine/threonine phosphatase-containing complex by syndecan-4 are downstream events of FGF2 signaling. (PMID:12011116)
• SDC4 regulates inositol phospholipid binding and signaling (PMID:12377772)
• the focal adhesion component alpha-actinin interacts with syndecan-4 in a beta-integrin-independent manner (PMID:12493766)
• Syndecan-4 can promote cell spreading in a beta(1) integrin-dependent fashion through PKCalpha and RhoA (PMID:12509413)
• endotoxin-induced adhesion of leukocytes to endothelium can be reversed by ligation of syndecan-4 with antithrombin’s heparin-binding site (PMID:14652650)
• syndecan-4/CXCR4 complex is likely a functional unit involved in SDF-1 binding (PMID:15033938)
• human trabecular meshwork cells express only syndecan-1, and not syndecan-4, at the cell surface, and focal adhesion and stress fiber formation occur independent of syndecan-4 (PMID:15572366)
• Syndecan-4 has a critical role in thrombin-induced migration and proliferation in human vascular smooth muscle cells (PMID:15731100)
• CXCL12 directly binds to syndecan-4 in a glycosaminoglycan-dependent manner (PMID:15819887)
• may play important roles in the regulation of inflammatory effects of platelets (PMID:15968398)
• Plasmin and thrombin accelerate shedding of syndecan-4 ectodomain, which generates cleavage sites at Lys(114)-Arg(115) and Lys(129)-Val(130) bonds (PMID:16087677)
• the transmembrane domains are sufficient for inducing dimerization and transmembrane domain-induced oligomerization is crucial for syndecan-2 and syndecan-4 functions (PMID:16253987)
• The H. pylori- and TLR-induced increase in syndecan-4 mRNA was blocked by the proteosome inhibitor MG-132 suggesting a role for nuclear factor kappaB (NF-kappaB) in the regulation of syndecan-4 gene expression (PMID:16319082)
• Syndecan-1 and syndecan-4 may have roles in progression of breast carcinoma (PMID:16636895)
• Stress-induced effects on smooth muscle cell syndecan-4 expression and shedding may represent an additional component of proinflammatory, growth-stimulating pathways activated in response to changes in the mechanical microenvironment of the vascular wall. (PMID:16822948)
• The expression of syndecan-4 protein was significantly enhanced by TNF-alpha in HUVECs. (PMID:17545042)
• An alternate pathway mediated by the extracellular domains of syndecans-2 and -4 is characterized that is independent of both heparan sulphate and syndecan signaling. (PMID:17870067)
• These results identify syndecan-4 as a novel receptor for the N-terminus of TSP-1 and suggest that TSP-1 N-terminal pro-angiogenic activity is linked to its capacity of interfering with syndecan-4 functions in the course of cell adhesion. (PMID:17879962)
• analysis of how a peptide derived from tenascin-C induces beta1 integrin activation through syndecan-4 (PMID:17901052)
• syndecan TMD homodimerization and heterodimerization can be mediated by GxxxG motifs and modulated by sequence context (PMID:18093920)
• syndecan-4 is a critical intrinsic regulator of inflammatory reactions via its effects on OPN function (PMID:18158320)
• This study provides evidence for the up-regulation of syndecan-2 and -4 in human primary CD4 T cells during in vitro activation and suggest an inhibitory role for these syndecans in CD4 T cells. (PMID:18342939)
• TG-FN binding to syndecan-4 activates PKCalpha leading to its association with beta(1) integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation (PMID:18499669)
• None of the SDC4 polymorphisms showed a difference in their allelic distribution between leg ulcer patients and controls. SDC4 may play a role in wound healing, but expression abnormalities in uninvolved dermis may contribute to venous ulcer development. (PMID:18638267)
• ADAMTS1, involved in angiogenesis and inflammatory processes, cleaves the ectodomain of syndecan-4. This cleavage results in altered distribution of cytoskeleton components, functional loss of adhesion, and gain of migratory capacities. (PMID:18775505)
• SD-4 is the T-cell ligand of DC-HIL. (PMID:19350579)
• The present study shows that highly pathogenic H. pylori strains induce syndecan-4 expression, both in human gastric mucosa and in gastric cell lines, in a cag pathogenicity island-dependent manner. (PMID:19519784)
• Syndecan-4 may be a sensor of tension exerted on the matrix [review] (PMID:19538537)
• Study indicates that SDC-1 and -4 may be required for HepG2, Hep3B and Huh7 human hepatoma cell migration, invasion or spreading induced by the chemokine. (PMID:19632304)
• syndecan-4 is specifically induced in type X collagen-producing chondrocytes in osteoarthritis (PMID:19684582)
• The down-regulation of syndecan-4, a heparan sulfate proteoglycan, decreased SDF-1/CXCL12-mediated HeLa cell invasion. (PMID:19695308)
• syndecan 1 and 4 correlate to increased metastatic potential in melanoma patients and are an important component of the Wnt5A autocrine signaling loop (PMID:19696445)
• Study identified an overrepresentation of focal amplifications of known (FGFR3, CCND1, MYC, MDM2) and novel candidate genes (MYBL2, YWHAB and SDC4) in stage Ta bladder carcinoma. (PMID:19821490)
• Data report that the bFGF, FGFR1/2 and syndecan 1-4 expressions are altered in bladder tumours. (PMID:19822079)
• ADAM17 may therefore be an important regulator of syndecan functions on inflamed lung epithelium. (PMID:19875451)
• SDC4 promotes cytokinesis in a phosphorylation-dependent manner in MCF-7 breast adenocarcinoma cells. The serine179-phosphorylation and the ectodomain shedding of SDC4 changed periodically in a cell cycle-dependent way. (PMID:20229236)
• Expression of syndecan 4 in healthy human breast tissue during menstrual cycle. (PMID:20398359)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sdc4	ENSDARG00000059906
mus_musculus	Sdc4	ENSMUSG00000017009
rattus_norvegicus	Sdc4	ENSRNOG00000014297
drosophila_melanogaster	Sdc	FBGN0010415
caenorhabditis_elegans		WBGENE00004749

Paralogs (3): SDC1 (ENSG00000115884), SDC3 (ENSG00000162512), SDC2 (ENSG00000169439)

Protein

Protein identifiers

Syndecan-4 — P31431 (reviewed: P31431)

Alternative names: Amphiglycan, Ryudocan core protein

All UniProt accessions (1): P31431

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface proteoglycan which regulates exosome biogenesis in concert with SDCBP and PDCD6IP.

Subunit / interactions. Homodimer. Interacts (via its cytoplasmic domain) with GIPC (via its PDZ domain). Interacts (via its cytoplasmic domain) with NUDT16L1. Interacts with CDCP1 and SDCBP. Interacts with DNM2; this interaction is markedly enhanced at focal ahesion site upon induction of focal adhesions and stress-fiber formation.

Subcellular location. Membrane. Secreted Secreted.

Tissue specificity. Detected in fibroblasts (at protein level). Also expressed in epithelial cells.

Post-translational modifications. Shedding is enhanced by a number of factors such as heparanase, thrombin or EGF. Also by stress and wound healing. PMA-mediated shedding is inhibited by TIMP3. O-glycosylated; contains both chondroitin sulfate and heparan sulfate. Ser-39, Ser-61 and Ser-63 can all be modified by either chondroitin sulfate or heparan sulfate, and the protein exists in forms that contain only chondroitin sulfate, only heparan sulfate and both chondroitin sulfate and heparan sulfate.

Miscellaneous. Soluble form, lacks the transmembrane domain.

Similarity. Belongs to the syndecan proteoglycan family.

Isoforms (2)

UniProt ID	Names	Canonical?
P31431-1	1	yes
P31431-2	2

RefSeq proteins (1): NP_002990* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001050	Syndecan	Family
IPR003585	Neurexin-like	Domain
IPR027789	Syndecan/Neurexin_dom	Domain
IPR030479	Syndecan_CS	Conserved_site

Pfam: PF01034

UniProt features (13 total): glycosylation site 4, strand 2, topological domain 2, signal peptide 1, chain 1, sequence variant 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8BLV	X-RAY DIFFRACTION	1.5
1OBY	X-RAY DIFFRACTION	1.85
1YBO	X-RAY DIFFRACTION	2.3
1EJP	SOLUTION NMR
1EJQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31431-F1	63.45	0.08

Functional residue map

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

Glycosylation sites (4): 39, 61, 63, 95

Function

Pathways and Gene Ontology

Reactome pathways

40 pathways

ID	Pathway
R-HSA-1971475	Glycosaminoglycan-protein linkage region biosynthesis
R-HSA-2022928	HS-GAG biosynthesis
R-HSA-2024096	HS-GAG degradation
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-3000170	Syndecan interactions
R-HSA-3560783	Defective B4GALT7 causes EDS, progeroid type
R-HSA-3560801	Defective B3GAT3 causes JDSSDHD
R-HSA-3656237	Defective EXT2 causes exostoses 2
R-HSA-3656253	Defective EXT1 causes exostoses 1, TRPS2 and CHDS
R-HSA-4420332	Defective B3GALT6 causes EDSP2 and SEMDJL1
R-HSA-9694614	Attachment and Entry
R-HSA-975634	Retinoid metabolism and transport
R-HSA-9769735	Initiation of coagulation cascade
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9820960	Respiratory syncytial virus (RSV) attachment and entry
R-HSA-9833110	RSV-host interactions
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-9918485	Dengue Virus Attachment and Entry
R-HSA-109582	Hemostasis
R-HSA-1430728	Metabolism
R-HSA-1474244	Extracellular matrix organization
R-HSA-1630316	Glycosaminoglycan metabolism
R-HSA-1638091	Heparan sulfate/heparin (HS-GAG) metabolism
R-HSA-1643685	Disease
R-HSA-1793185	Chondroitin sulfate/dermatan sulfate metabolism
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2187338	Visual phototransduction
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-3560782	Diseases associated with glycosaminoglycan metabolism
R-HSA-3781865	Diseases of glycosylation

MSigDB gene sets: 547 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, CREL_01, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_VESICLE_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_VESICLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP

GO Biological Process (11): ureteric bud development (GO:0001657), neural tube closure (GO:0001843), regulation of fibroblast migration (GO:0010762), cell migration (GO:0016477), wound healing (GO:0042060), negative regulation of T cell proliferation (GO:0042130), positive regulation of stress fiber assembly (GO:0051496), positive regulation of focal adhesion assembly (GO:0051894), inner ear receptor cell stereocilium organization (GO:0060122), positive regulation of exosomal secretion (GO:1903543), positive regulation of extracellular exosome assembly (GO:1903553)

GO Molecular Function (5): fibronectin binding (GO:0001968), protein kinase C binding (GO:0005080), identical protein binding (GO:0042802), thrombospondin receptor activity (GO:0070053), protein binding (GO:0005515)

GO Cellular Component (9): Golgi lumen (GO:0005796), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell surface (GO:0009986), costamere (GO:0043034), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Diseases associated with glycosaminoglycan metabolism	5
Heparan sulfate/heparin (HS-GAG) metabolism	2
Coagulation pathway	2
Respiratory Syncytial Virus Infection Pathway	2
Dengue Virus Infection	2
Glycosaminoglycan metabolism	1
Hemostasis	1
Non-integrin membrane-ECM interactions	1
Early SARS-CoV-2 Infection Events	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	2
mesonephric tubule development	1
primary neural tube formation	1
tube closure	1
fibroblast migration	1
regulation of cell migration	1
cell motility	1
response to wounding	1
tissue regeneration	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
positive regulation of cell-matrix adhesion	1
focal adhesion assembly	1
regulation of focal adhesion assembly	1
positive regulation of cell-substrate junction organization	1
positive regulation of cell junction assembly	1
neuron projection development	1
inner ear receptor cell development	1
positive regulation of cellular component biogenesis	1
positive regulation of exocytosis	1
regulation of exosomal secretion	1
exosomal secretion	1
extracellular exosome assembly	1
positive regulation of organelle assembly	1
regulation of extracellular exosome assembly	1
protein kinase binding	1
signaling receptor activity	1
binding	1
Golgi apparatus	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
cell-substrate junction	1
myofibril	1

Protein interactions and networks

STRING

1590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SDC4	FN1	P02751	992
SDC4	FZD7	O75084	982
SDC4	PRKCA	P17252	973
SDC4	FGF2	P09038	971
SDC4	GIPC1	O14908	964
SDC4	THY1	P04216	936
SDC4	ADAMTS5	Q9UNA0	933
SDC4	FGFR1	P11362	887
SDC4	RSPO3	Q9BXY4	845
SDC4	TRAPPC4	Q9Y296	828
SDC4	FGF13	Q92913	820
SDC4	CCN2	P29279	787
SDC4	EGFR	P00533	785
SDC4	GPNMB	Q14956	775
SDC4	THBS1	P07996	773
SDC4	GPC1	P35052	773

IntAct

253 interactions, top by confidence:

A	B	Type	Score
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
SDC4	SGTA	psi-mi:“MI:0915”(physical association)	0.720
SGTA	SDC4	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SDC4	SDC2	psi-mi:“MI:0407”(direct interaction)	0.690
SDC2	SDC4	psi-mi:“MI:0407”(direct interaction)	0.690
SDC2	PDPK1	psi-mi:“MI:0914”(association)	0.640
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
S	SDC4	psi-mi:“MI:0403”(colocalization)	0.600
S	SDC4	psi-mi:“MI:0915”(physical association)	0.600
SDC4	SGTB	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (91): SGTA (Two-hybrid), SDC4 (Affinity Capture-MS), SDC4 (Reconstituted Complex), SDC4 (Affinity Capture-MS), SDC4 (Affinity Capture-MS), SDC4 (Two-hybrid), RARRES3 (Affinity Capture-Western), SDC4 (Affinity Capture-Western), SDC4 (Affinity Capture-Western), SDC4 (Affinity Capture-MS), SDC4 (Affinity Capture-MS), SDC4 (Reconstituted Complex), SDC4 (Co-purification), SDC4 (Affinity Capture-MS), SDC4 (Affinity Capture-MS)

ESM2 similar proteins: A1A4K1, B1H3G4, E9PV24, O35988, O61704, O75167, O93383, P14209, P14599, P15514, P24338, P31431, P31955, P34741, P34900, P34901, P43322, P43407, P49414, P49416, P50605, P55808, P58239, Q02297, Q0VFF9, Q1RMT9, Q27913, Q56A20, Q58DD4, Q5RAT9, Q5RCS3, Q5RE35, Q5REP3, Q5XG99, Q6DBW9, Q6GR51, Q6PKG0, Q6ZQ58, Q7SXB3, Q7TMJ8

Diamond homologs: O35988, O75056, P18827, P18828, P26260, P26261, P31431, P33671, P34740, P34741, P34900, P34901, P43407, P47951, P49414, P49415, P49416, Q08DZ5, Q1AGV6, Q1AGV7, Q58DD4, Q5RAT9, Q64519, Q6GR51, Q8HZJ6, P50605

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
RSPO2	up-regulates	SDC4	binding
RSPO3	up-regulates	SDC4	binding
SDC4	up-regulates	DVL1	binding
SDC4	up-regulates	DVL2	binding
SDC4	up-regulates	DVL3	binding
F2RL1	“up-regulates quantity by expression”	SDC4	“transcriptional regulation”
F2R	“up-regulates quantity by expression”	SDC4	“transcriptional regulation”
FN1	“up-regulates activity”	SDC4	binding
SDC4	“form complex”	FZD7/SDC4	binding
SDC4	“up-regulates activity”	RAC1	binding
“Integrator complex”	“down-regulates quantity by repression”	SDC4	“transcriptional regulation”
ADAM12	up-regulates	SDC4	binding
PRKCD	“up-regulates activity”	SDC4	phosphorylation
PRKCA	“up-regulates activity”	SDC4	phosphorylation
SDC4	“form complex”	FN1/SDC4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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
Attachment and Entry	5	27.6×	2e-04
Protein-protein interactions at synapses	8	19.5×	2e-06
Neurexins and neuroligins	10	18.1×	1e-07
Glycosaminoglycan-protein linkage region biosynthesis	5	18.1×	7e-04
EPHB-mediated forward signaling	5	12.2×	2e-03
Assembly and cell surface presentation of NMDA receptors	5	11.6×	2e-03
Regulation of clotting cascade	5	10.7×	2e-03
Non-integrin membrane-ECM interactions	7	9.9×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	8	31.4×	1e-07
protein localization to synapse	6	31.1×	1e-05
receptor clustering	7	29.5×	2e-06
cell-cell junction organization	5	21.1×	6e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	6	20.1×	1e-04
positive regulation of ERK1 and ERK2 cascade	10	5.8×	1e-03
cell-cell adhesion	8	5.5×	8e-03
actin cytoskeleton organization	9	4.8×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

553 predictions. Top by Δscore:

Variant	Effect	Δscore
20:45327411:CAGAG:C	acceptor_gain	1.0000
20:45327412:AGAG:A	acceptor_gain	1.0000
20:45327413:GAG:G	acceptor_gain	1.0000
20:45327414:AG:A	acceptor_gain	1.0000
20:45327415:GCT:G	acceptor_loss	1.0000
20:45327416:C:CC	acceptor_gain	1.0000
20:45327416:C:CG	acceptor_loss	1.0000
20:45327417:T:A	acceptor_loss	1.0000
20:45330361:CTTA:C	donor_loss	1.0000
20:45330363:TA:T	donor_loss	1.0000
20:45330364:A:AC	donor_gain	1.0000
20:45330364:ACCTG:A	donor_gain	1.0000
20:45330365:C:A	donor_loss	1.0000
20:45330365:C:CC	donor_gain	1.0000
20:45330365:CCTG:C	donor_gain	1.0000
20:45330365:CCTGC:C	donor_gain	1.0000
20:45330560:GGCAC:G	acceptor_gain	1.0000
20:45330562:CAC:C	acceptor_gain	1.0000
20:45330563:AC:A	acceptor_gain	1.0000
20:45330564:CC:C	acceptor_gain	1.0000
20:45330565:C:CA	acceptor_loss	1.0000
20:45330565:C:CC	acceptor_gain	1.0000
20:45330566:T:A	acceptor_loss	1.0000
20:45330574:C:CT	acceptor_gain	1.0000
20:45330575:G:T	acceptor_gain	1.0000
20:45333018:CTTA:C	donor_loss	1.0000
20:45333019:TTA:T	donor_loss	1.0000
20:45333020:TA:T	donor_loss	1.0000
20:45333021:A:AC	donor_gain	1.0000
20:45333021:A:T	donor_loss	1.0000

AlphaMissense

1287 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:45327392:C:G	G157R	0.981
20:45327273:G:C	F196L	0.980
20:45327273:G:T	F196L	0.980
20:45327275:A:G	F196L	0.980
20:45327391:C:T	G157D	0.972
20:45327401:C:G	G154R	0.966
20:45327379:G:T	A161D	0.955
20:45327349:C:G	R171P	0.954
20:45327268:G:T	A198E	0.953
20:45327299:A:C	Y188D	0.948
20:45327415:G:T	A149D	0.948
20:45327404:C:G	G153R	0.947
20:45327291:T:A	K190N	0.944
20:45327291:T:G	K190N	0.944
20:45327400:C:T	G154D	0.940
20:45327274:A:C	F196C	0.938
20:45327274:A:G	F196S	0.934
20:45327403:C:T	G153D	0.920
20:45327269:C:G	A198P	0.919
20:45327324:G:C	S179R	0.919
20:45327324:G:T	S179R	0.919
20:45327326:T:G	S179R	0.919
20:45327292:T:A	K190I	0.914
20:45327412:A:G	L150P	0.911
20:45327299:A:G	Y188H	0.909
20:45327339:C:A	K174N	0.906
20:45327339:C:G	K174N	0.906
20:45327289:G:T	A191D	0.905
20:45327299:A:T	Y188N	0.904
20:45327342:C:A	K173N	0.898

dbSNP variants (sampled 300 via entrez): RS1000247104 (20:45330063 A>T), RS1000429595 (20:45346310 G>C), RS1000532198 (20:45328181 C>T), RS1000799643 (20:45347521 C>T), RS1000856150 (20:45340780 G>A), RS1000892499 (20:45340117 A>G), RS1001120004 (20:45346220 G>A), RS1001169714 (20:45347802 A>G), RS1001289978 (20:45346791 G>A), RS1001547856 (20:45346916 G>A), RS1001756873 (20:45330526 A>G), RS1001987918 (20:45328554 G>A,T), RS1002102642 (20:45330218 T>A), RS1002245428 (20:45340754 G>A), RS1002252089 (20:45336079 G>A,C)

Disease associations

OMIM: gene MIM:600017 | disease phenotypes: MIM:125853

GenCC curated gene-disease

Mondo (1): type 2 diabetes mellitus (MONDO:0005148)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000834_1	Psoriasis	1.000000e-07
GCST010725_40	Malaria	1.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5303568 (CHIMERIC PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 20,037 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL601719	CRIZOTINIB	4	14,403

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.80	IC50	16	nM	BRIGATINIB
7.77	IC50	17	nM	CRIZOTINIB

PubChem BioAssay actives

2 with measured affinity, of 3 total; 2 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
Brigatinib	2183016: Inhibition of SDC4-ROS1 (unknown origin) expressed in mouse BaF3 cells assessed as inhibition of ROS1-driven cell viability incubated for 72 hrs by CellTiter 96 aqueous one solution assay	ic50	0.0160	uM
Crizotinib	2183016: Inhibition of SDC4-ROS1 (unknown origin) expressed in mouse BaF3 cells assessed as inhibition of ROS1-driven cell viability incubated for 72 hrs by CellTiter 96 aqueous one solution assay	ic50	0.0170	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Zoledronic Acid	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Atrazine	increases expression	2
Cisplatin	increases expression	2
Estradiol	decreases expression, affects binding, increases expression	2
Lipopolysaccharides	increases expression, affects expression, affects response to substance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	increases expression	2
Cyclosporine	increases expression	2
Glupearl 19S	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
kojic acid	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
nickel chloride	increases expression	1
manganese chloride	increases expression, increases abundance	1
bleomycetin	increases expression	1
cupric chloride	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2’-naphthyl)alanylalanine, 2-aminoethylamide	affects cotreatment, decreases reaction, increases secretion, decreases secretion	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5705246	Binding	Inhibition of SDC4-ROS1 (unknown origin) expressed in mouse BaF3 cells assessed as inhibition of ROS1-driven cell viability incubated for 72 hrs by CellTiter 96 aqueous one solution assay	The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. — Clin Cancer Res

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7ZA	Abcam Raji SDC4 KO	Cancer cell line	Male
CVCL_C0A3	Abcam THP-1 SDC4 KO	Cancer cell line	Male
CVCL_C7BR	Abcam PC-3 SDC4 KO	Cancer cell line	Male
CVCL_E2JQ	HAP1 SDC4 (-)	Cancer cell line	Male
CVCL_E6J5	ADK-VR2	Cancer cell line	Male
CVCL_E6J6	ADK-VR2 AG143	Cancer cell line	Male
CVCL_RY68	293_hSyn4	Transformed cell line	Female
CVCL_UJ34	CUTO-2	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus