GCSAM

Summary

GCSAM (germinal center associated signaling and motility, HGNC:20253) is a protein-coding gene on chromosome 3q13.2, encoding Germinal center-associated signaling and motility protein (Q8N6F7). Involved in the negative regulation of lymphocyte motility.

This gene encodes a protein which may function in signal transduction pathways and whose expression is elevated in germinal cell lymphomas. It contains a putative PDZ-interacting domain, an immunoreceptor tyrosine-based activation motif (ITAM), and two putative SH2 binding sites. In B cells, its expression is specifically induced by interleukin-4. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 257144 — RefSeq curated summary.

At a glance

• MANE Select transcript: NM_152785

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20253
Approved symbol	GCSAM
Name	germinal center associated signaling and motility
Location	3q13.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC40441, HGAL
Ensembl gene	ENSG00000174500
Ensembl biotype	protein_coding
OMIM	607792
Entrez	257144

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 nonsense_mediated_decay

ENST00000308910, ENST00000460387, ENST00000470085, ENST00000484193, ENST00000487901, ENST00000488580, ENST00000495418

RefSeq mRNA: 3 — MANE Select: NM_152785 NM_001190259, NM_001190260, NM_152785

CCDS: CCDS2964, CCDS54621, CCDS54622

Canonical transcript exons

ENST00000308910 — 6 exons

Exon	Start	End
ENSE00001200221	112128017	112128061
ENSE00001814703	112133092	112133248
ENSE00001871391	112120839	112123772
ENSE00003498790	112126987	112127033
ENSE00003506295	112125226	112125254
ENSE00003538221	112130445	112130513

Expression profiles

Bgee: expression breadth ubiquitous, 126 present calls, max score 91.44.

FANTOM5 (CAGE): breadth broad, TPM avg 4.1891 / max 539.2989, expressed in 250 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43729	3.9308	238
43730	0.1143	50
43727	0.0805	30
43728	0.0634	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	91.44	gold quality
skin of leg	UBERON:0001511	88.12	gold quality
zone of skin	UBERON:0000014	88.05	gold quality
skin of abdomen	UBERON:0001416	88.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.89	gold quality
vermiform appendix	UBERON:0001154	84.70	gold quality
body of pancreas	UBERON:0001150	84.42	gold quality
tonsil	UBERON:0002372	80.68	gold quality
rectum	UBERON:0001052	80.32	gold quality
granulocyte	CL:0000094	79.34	gold quality
pancreas	UBERON:0001264	78.42	gold quality
left lobe of thyroid gland	UBERON:0001120	77.43	gold quality
thyroid gland	UBERON:0002046	77.42	gold quality
blood	UBERON:0000178	76.34	gold quality
bone marrow cell	CL:0002092	75.79	gold quality
right lobe of thyroid gland	UBERON:0001119	75.44	gold quality
mucosa of transverse colon	UBERON:0004991	75.16	gold quality
body of stomach	UBERON:0001161	74.82	gold quality
stomach	UBERON:0000945	74.16	gold quality
spleen	UBERON:0002106	73.87	gold quality
duodenum	UBERON:0002114	73.50	gold quality
upper lobe of left lung	UBERON:0008952	72.74	gold quality
bone marrow	UBERON:0002371	72.20	gold quality
fundus of stomach	UBERON:0001160	72.09	gold quality
colonic epithelium	UBERON:0000397	71.91	gold quality
gall bladder	UBERON:0002110	71.73	gold quality
small intestine Peyer’s patch	UBERON:0003454	71.69	gold quality
transverse colon	UBERON:0001157	71.46	gold quality
small intestine	UBERON:0002108	71.12	gold quality
lung	UBERON:0002048	70.50	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PRDM1

miRNA regulators (miRDB)

117 targeting GCSAM, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-1197	99.70	67.75	1027

Literature-anchored findings (GeneRIF, showing 24)

• gene is induced by IL4 and expression strongly predicts survival in diffuse large B-cell lymphoma (PMID:12509382)
• results report the cloning of HGAL, a germinal center its expression pattern in normal tissues and hematologic malignancies, its induction by IL4, and the prognostic significance of its expression in predicting survival in diffuse large B-cell lymphoma (PMID:12509382)
• Results report the cloning of germinal center B-cell expressed transcripts 1 and 2 (GCET1 and 2), and show that both are expressed in follicular lymphoma and diffuse large B-cell lymphoma with germinal center B-cell differentiation (PMID:12819018)
• The restricted expression and germinal center specificity of HGAL protein suggest that it may have an important role in the diagnosis of specific lymphomas (PMID:15677569)
• HGAL is involved in negative regulation of lymphocyte migration, thus constraining lymphocytes to the germinal center (PMID:17823310)
• The correlation of HGAL expression with the germinal center B-cell phenotype demonstrates the role of this marker in the classification of cutaneous large B-cell lymphomas (PMID:18264083)
• Study confirms and validates findings of a correlation between HGAL expression and outcome in classical HL. (PMID:19883310)
• Our results show that HGAL and LMO2 are sensitive markers for follicular lymphoma diagnosis. (PMID:20697248)
• molecular mechanism underlying the inhibitory effects of germinal center-specific HGAL protein on the motility of GC-derived lymphoma cells (PMID:20844236)
• show that HGAL increases the binding of myosin to F-actin and inhibits the ability of myosin to translocate actin by reducing the maximal velocity of myosin head/actin movement (PMID:21447067)
• necessary for germinal center maintenance and confining B-cells to the germinal center microenvironment (PMID:21475040)
• HGAL is sensitive and specific marker for detecting follicular lymphoma in nodal and extranodal sites (PMID:21502424)
• Data suggest that both HGAL and LMO2 are directly regulated by the transcription repressor PRDM1–overexpression of PRDM1 down-regulates HGAL and LMO2; PRDM1 directly binds to promoters of both HGAL and LMO2 and represses genetic transcription. (PMID:21722313)
• Immunostaining for HGAL was more frequently positive than that for BCL6 and CD10 in follicular lymphomas (PMID:21988858)
• HGAL/GCET2 protein expression may function as a marker for germinal center B-cell type diffuse large B-cell lymphoma. (PMID:22743653)
• HGAL and LMO2 may be useful adjuncts in the identification of follicular lymphoma of the nongastric gastrointestinal tract. (PMID:22914613)
• the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation. (PMID:23299888)
• Diagnostic Utility of the Germinal Center-associated Markers GCET1, HGAL, and LMO2 in Hematolymphoid Neoplasms. (PMID:25203428)
• These findings further elucidate the growing and complex role of HGAL in B-cell biology and suggest that membrane-bound and cytoplasmic HGAL protein differently regulates distinct biological processes. (PMID:25381061)
• we have demonstrated that Grb2 directly interacts with phosphorylated HGAL, collaborating in cSMAC formation while oppositely regulating BCR-induced intracellular biochemical signaling. These interactions may play an important function in regulating the magnitude of BCR signaling and antigen presentation. (PMID:31362927)
• Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL. (PMID:31570756)
• Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice. (PMID:33024996)
• HGAL inhibits lymphoma dissemination by interacting with multiple cytoskeletal proteins. (PMID:34543391)
• Value of GCET1, HGAL (GCET2), and LMO2 in the Determination of Germinal Center Phenotype in Diffuse Large B-cell Lymphoma. (PMID:37519110)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gcsam	ENSMUSG00000022659
rattus_norvegicus	Gcsam	ENSRNOG00000022110

Paralogs (1): GCSAML (ENSG00000169224)

Protein

Protein identifiers

Germinal center-associated signaling and motility protein — Q8N6F7 (reviewed: Q8N6F7)

Alternative names: Germinal center B-cell-expressed transcript 2 protein, Germinal center-associated lymphoma protein

All UniProt accessions (3): Q8N6F7, C9JY41, F2Z3F7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the negative regulation of lymphocyte motility. It mediates the migration-inhibitory effects of IL6. Serves as a positive regulator of the RhoA signaling pathway. Enhancement of RhoA activation results in inhibition of lymphocyte and lymphoma cell motility by activation of its downstream effector ROCK. Is a regulator of B-cell receptor signaling, that acts through SYK kinase activation.

Subunit / interactions. Interacts with ACTB and MYH2; the interaction with MYH2 is increased by IL6-induced phosphorylation. Interacts (via C-terminus) with ARHGEF11 (via DH domain). Interacts with ARHGEF12. Interacts with SYK; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in diffuse large B-cell lymphoma (DLBCL) and several germinal center (GC)-like lymphoma cell lines (at protein level). Highly expressed in normal GC lymphocytes and GC-derived malignancies. Expressed in thymus and spleen.

Post-translational modifications. Phosphorylation on tyrosine residues can be induced by IL6. Phosphorylation is mediated by LYN. Targeted by the ubiquitin E3 ligase subunit FBXO10 to mediate its ubiquitination and degradation.

Induction. Up-regulated by IL4/interleukin-4.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N6F7-1	1	yes
Q8N6F7-2	2
Q8N6F7-3	3

RefSeq proteins (3): NP_001177188, NP_001177189, NP_689998* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031364	GC_assoc_lym	Family

Pfam: PF15666

UniProt features (9 total): mutagenesis site 4, modified residue 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N6F7-F1	56.87	0.00

Functional residue map

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

Post-translational modifications (2): 99, 148

Mutagenesis-validated functional residues (4):

Position	Phenotype
91	loss of fbxo10-mediated ubiquitination and degradation.
106–107	does not affect the interaction with syk.
128	does not affect il6 induced phosphorylation. does not affect the interaction with syk.
148	prevents il6 induced phosphorylation. does not affect the interaction with syk.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): GOBP_REGULATION_OF_B_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, LU_IL4_SIGNALING, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_REGULATION_OF_MONONUCLEAR_CELL_MIGRATION, GOBP_LEUKOCYTE_MIGRATION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MIGRATION, GOMF_ACTIN_BINDING, GOBP_LYMPHOCYTE_MIGRATION, GOBP_B_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LYMPHOCYTE_MIGRATION, GOMF_CYTOSKELETAL_PROTEIN_BINDING, GOMF_KINASE_BINDING

GO Biological Process (3): regulation of B cell receptor signaling pathway (GO:0050855), negative regulation of lymphocyte migration (GO:2000402), regulation of lymphocyte migration (GO:2000401)

GO Molecular Function (4): actin binding (GO:0003779), protein kinase binding (GO:0019901), myosin II binding (GO:0045159), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymphocyte migration	2
cellular anatomical structure	2
B cell receptor signaling pathway	1
regulation of antigen receptor-mediated signaling pathway	1
negative regulation of mononuclear cell migration	1
regulation of lymphocyte migration	1
regulation of mononuclear cell migration	1
cytoskeletal protein binding	1
kinase binding	1
myosin binding	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCSAM	NISCH	Q9Y2I1	668
GCSAM	LMO2	P25791	580
GCSAM	BCL6	P41182	575
GCSAM	TMEM14A	Q9Y6G1	536
GCSAM	SYK	P43405	518
GCSAM	PPM1N	Q8N819	508
GCSAM	SERPINA9	Q86WD7	506
GCSAM	CLNK	Q7Z7G1	500
GCSAM	SNX22	Q96L94	496
GCSAM	HLA-A	P01891	494
GCSAM	PHYH	O14832	492
GCSAM	HLA-B	P01889	492
GCSAM	LGALS8	O00214	491
GCSAM	FGD6	Q6ZV73	484
GCSAM	MME	P08473	476

IntAct

17 interactions, top by confidence:

A	B	Type	Score
GCSAM	APPBP2	psi-mi:“MI:0915”(physical association)	0.720
APPBP2	GCSAM	psi-mi:“MI:0915”(physical association)	0.720
CYSRT1	GCSAM	psi-mi:“MI:0915”(physical association)	0.560
GCSAM	AP1M1	psi-mi:“MI:0915”(physical association)	0.560
GCSAM	CNOT2	psi-mi:“MI:0915”(physical association)	0.560
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
GCSAM	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000
GCSAM	APPBP2	psi-mi:“MI:0915”(physical association)	0.000
AP1M1	GCSAM	psi-mi:“MI:0915”(physical association)	0.000
CNOT2	GCSAM	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): GCSAM (Two-hybrid), GCSAM (Two-hybrid), GCSAM (Two-hybrid), GCSAM (Two-hybrid), CYSRT1 (Two-hybrid), GCSAM (Affinity Capture-MS), GCSAM (Affinity Capture-Western), GCSAM (Affinity Capture-Western), GCSAM (Affinity Capture-Western), FBXO10 (Affinity Capture-Western), GCSAM (Biochemical Activity)

ESM2 similar proteins: A0JNM1, D3Z1Q2, P16871, P20963, P24161, P29329, P59773, Q16655, Q29102, Q2KIP5, Q2YDG7, Q3SYX1, Q3U1F9, Q3UU41, Q3UU67, Q4W815, Q5DTU0, Q5E9I3, Q5JQS6, Q6ITQ4, Q6PF55, Q6PIZ9, Q6RFH4, Q6UWF3, Q6XQ84, Q6ZUJ8, Q6ZWK4, Q80VH0, Q80WK2, Q86UW2, Q8C115, Q8C4Q9, Q8CB93, Q8N292, Q8N4X5, Q8N6F7, Q8NDB2, Q8NEA5, Q90479, Q90VY2

Diamond homologs: Q5JQS6, Q6RFH4, Q8N6F7

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
GCSAM	“down-regulates activity”	GRB2	binding
LYN	“up-regulates activity”	GCSAM	phosphorylation
SYK	“up-regulates activity”	GCSAM	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

889 predictions. Top by Δscore:

Variant	Effect	Δscore
3:112126980:GACTT:G	donor_loss	1.0000
3:112126981:ACTT:A	donor_loss	1.0000
3:112126982:CTTAC:C	donor_loss	1.0000
3:112126983:TTA:T	donor_loss	1.0000
3:112126984:TA:T	donor_loss	1.0000
3:112126985:A:AC	donor_gain	1.0000
3:112126985:ACTTT:A	donor_gain	1.0000
3:112126986:C:CT	donor_gain	1.0000
3:112126986:CT:C	donor_gain	1.0000
3:112126986:CTT:C	donor_gain	1.0000
3:112126986:CTTT:C	donor_gain	1.0000
3:112126986:CTTTC:C	donor_gain	1.0000
3:112126989:T:A	donor_gain	1.0000
3:112127029:TTTTC:T	acceptor_gain	1.0000
3:112127030:TTTC:T	acceptor_gain	1.0000
3:112127034:C:A	acceptor_loss	1.0000
3:112127034:C:CC	acceptor_gain	1.0000
3:112127035:T:G	acceptor_loss	1.0000
3:112123777:T:C	acceptor_gain	0.9900
3:112127031:TTC:T	acceptor_gain	0.9900
3:112127032:TC:T	acceptor_gain	0.9900
3:112127032:TCCTG:T	donor_loss	0.9900
3:112127033:CC:C	acceptor_gain	0.9900
3:112127033:CCTGT:C	donor_loss	0.9900
3:112127034:CTGT:C	donor_loss	0.9900
3:112133087:CTTA:C	donor_loss	0.9900
3:112133088:TTAC:T	donor_loss	0.9900
3:112133089:TACCT:T	donor_loss	0.9900
3:112133091:C:CA	donor_loss	0.9900
3:112127005:G:A	donor_gain	0.9800

AlphaMissense

1172 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:112123610:A:G	Y128H	0.944
3:112123609:T:G	Y128S	0.930
3:112123610:A:C	Y128D	0.889
3:112123665:A:C	N109K	0.888
3:112123665:A:T	N109K	0.888
3:112123609:T:C	Y128C	0.840
3:112123610:A:T	Y128N	0.827
3:112123736:A:C	Y86D	0.807
3:112123550:A:G	Y148H	0.795
3:112123666:T:A	N109I	0.776
3:112123726:A:C	I89S	0.773
3:112123607:A:G	S129P	0.770
3:112123726:A:G	I89T	0.769
3:112123669:T:A	E108V	0.761
3:112123549:T:G	Y148S	0.757
3:112133117:C:G	G2R	0.753
3:112133117:C:T	G2R	0.753
3:112123603:A:G	L130P	0.740
3:112123615:G:A	T126I	0.736
3:112127031:T:A	K49I	0.731
3:112133100:T:A	R7S	0.729
3:112133100:T:G	R7S	0.729
3:112123467:A:C	F175L	0.727
3:112123467:A:T	F175L	0.727
3:112123469:A:G	F175L	0.727
3:112123736:A:T	Y86N	0.722
3:112123668:C:A	E108D	0.719
3:112123668:C:G	E108D	0.719
3:112123735:T:G	Y86S	0.706
3:112123666:T:G	N109T	0.692

dbSNP variants (sampled 300 via entrez): RS1000493452 (3:112128752 A>G), RS1000517943 (3:112124539 C>G,T), RS1000624320 (3:112134111 C>A,T), RS1000627903 (3:112125876 A>T), RS1000656944 (3:112133715 T>C), RS1000780052 (3:112127674 C>A), RS1001212420 (3:112127351 C>A,G), RS1001275828 (3:112128706 A>C), RS1001336057 (3:112129554 G>C), RS1001608762 (3:112134519 C>A), RS1001826936 (3:112134405 G>C), RS1001868790 (3:112121965 C>A,T), RS1002189201 (3:112123137 G>A), RS1003058510 (3:112127801 C>G,T), RS1003120660 (3:112128492 G>T)

Disease associations

OMIM: gene MIM:607792 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
gardiquimod	increases expression, decreases reaction	1
Benzo(a)pyrene	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Formaldehyde	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	decreases methylation	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Lactic Acid	increases expression	1
Protein Kinase Inhibitors	decreases reaction, increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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