GAB1

Summary

GAB1 (GRB2 associated binding protein 1, HGNC:4066) is a protein-coding gene on chromosome 4q31.21, encoding GRB2-associated-binding protein 1 (Q13480). Adapter protein that plays a role in intracellular signaling cascades triggered by activated receptor-type kinases.

The protein encoded by this gene is a member of the IRS1-like multisubstrate docking protein family. It is an important mediator of branching tubulogenesis and plays a central role in cellular growth response, transformation and apoptosis. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2549 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive nonsyndromic hearing loss 26 (Limited, GenCC)
• Clinical variants (ClinVar): 113 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_002039

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4066
Approved symbol	GAB1
Name	GRB2 associated binding protein 1
Location	4q31.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109458
Ensembl biotype	protein_coding
OMIM	604439
Entrez	2549

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 11 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000262994, ENST00000262995, ENST00000505913, ENST00000507070, ENST00000507334, ENST00000508833, ENST00000509992, ENST00000510615, ENST00000511109, ENST00000511836, ENST00000512843, ENST00000514639, ENST00000515366, ENST00000515388, ENST00000882511, ENST00000882512, ENST00000882513, ENST00000882514

RefSeq mRNA: 2 — MANE Select: NM_002039 NM_002039, NM_207123

CCDS: CCDS3759, CCDS3760

Canonical transcript exons

ENST00000262994 — 10 exons

Exon	Start	End
ENSE00000739496	143437999	143438600
ENSE00000927407	143466103	143466225
ENSE00001218331	143439802	143439887
ENSE00002041870	143469031	143474565
ENSE00002082371	143336876	143337260
ENSE00003467441	143460364	143460487
ENSE00003468084	143415477	143415771
ENSE00003619205	143440079	143440382
ENSE00003676083	143459385	143459478
ENSE00003789487	143433491	143433716

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 98.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.5282 / max 1188.4091, expressed in 1658 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49838	5.8045	1028
49834	2.9470	1010
49841	0.9984	447
49833	0.9471	502
49847	0.7967	159
49837	0.7195	284
49832	0.5187	257
49846	0.4009	97
49851	0.3015	104
49840	0.2690	116

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.89	gold quality
oocyte	CL:0000023	98.40	gold quality
colonic epithelium	UBERON:0000397	98.32	gold quality
endothelial cell	CL:0000115	97.04	gold quality
corpus callosum	UBERON:0002336	96.73	gold quality
ventricular zone	UBERON:0003053	96.34	gold quality
trigeminal ganglion	UBERON:0001675	95.98	gold quality
sural nerve	UBERON:0015488	95.41	gold quality
inferior vagus X ganglion	UBERON:0005363	94.27	gold quality
dorsal root ganglion	UBERON:0000044	93.50	gold quality
medial globus pallidus	UBERON:0002477	93.45	gold quality
tendon of biceps brachii	UBERON:0008188	93.31	gold quality
globus pallidus	UBERON:0001875	92.59	gold quality
calcaneal tendon	UBERON:0003701	91.99	gold quality
nerve	UBERON:0001021	91.98	gold quality
tibial nerve	UBERON:0001323	91.98	gold quality
subthalamic nucleus	UBERON:0001906	91.60	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.45	gold quality
rectum	UBERON:0001052	91.03	gold quality
spinal cord	UBERON:0002240	90.90	gold quality
tendon	UBERON:0000043	90.88	gold quality
ganglionic eminence	UBERON:0004023	90.23	gold quality
adrenal tissue	UBERON:0018303	90.16	gold quality
lower esophagus	UBERON:0013473	89.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.90	gold quality
descending thoracic aorta	UBERON:0002345	89.66	gold quality
pigmented layer of retina	UBERON:0001782	89.41	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.40	gold quality
retina	UBERON:0000966	89.39	gold quality
tibia	UBERON:0000979	89.22	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	86.84
E-MTAB-9067	yes	16.57
E-ANND-3	yes	14.58
E-MTAB-9543	yes	12.54
E-MTAB-7381	no	324.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

306 targeting GAB1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-27A-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 40)

• Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein. (PMID:11606067)
• comparative FISH mapping of Gab1 and Gab2 genes in human, mouse and rat (PMID:11701952)
• ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase (PMID:11896055)
• Results indicate that Gab1 and SHP-2 promote the undifferentiated epidermal cell state by facilitating Ras/MAPK signaling. (PMID:12370245)
• Gab1 and the Met receptor interact in a novel manner, such that the activated kinase domain of Met and the negative charge of phosphotyrosine 1349 engage the Gab1 MBD as an extended peptide ligand (PMID:12766170)
• Gab1 is an integrator of cell death versus cell survival signals in oxidative stress (PMID:12808090)
• Gab1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyoctes and cardiac hypertrophy through activation of ERK5 (PMID:12855672)
• results reveal that Gab1 protein recruits SHP2 protein tyrosine phosphatase to dephosphorylate paxillin (PMID:14665621)
• SHP-2/Gab1 association is critical for linking EGFR to NF-kappaB transcriptional activity via the PI3-kinase/Akt signaling axis in glioblastoma cells (PMID:14701753)
• Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells. (PMID:15010462)
• coupling of Gab1 to PI3K is important for biological responses in RET-expressing cells (PMID:15351743)
• extracellular signal-regulated kinases 1/2 modulate insulin action via Gab1 by targeting serine and threonine residues beside YXXM motifs (PMID:15379552)
• Gab1 tyrosine phosphorylation is stimulated by flow shear stress to mediate protein kinase B and endothelial nitric-oxide synthase activation in endothelial cells (PMID:15665327)
• RAI associates with the Grb 2-associated binder 1 (GAB 1) adapter. This association is constitutive, but, in the presence of RET oncoproteins, both RAI and GAB 1 are tyrosine-phosphorylated, and the stoichiometry of this interaction remarkably increases (PMID:15940252)
• Gab2 plays a pivotal role in the EGF-induced ERK activation pathway and that it can complement the function of Gab1 in the EGF signalling pathway; Gab1 and Gab2 are critical signalling threshold proteins for ERK activation by EGF. (PMID:15952937)
• By amplifying positive interactions between survival and mitogenic pathways, GAB1 plays the critical role in cell proliferation and tumorigenesis. (PMID:16687399)
• Gab1 appears as a primary actor in coupling VEGFR-2 to PI3K/Akt, recruited through an amplification loop involving PtdIns(3,4,5)P3 and its PH domain (PMID:16787925)
• Crk adaptor protein is required for the sustained phosphorylation of c-Met-docking protein Grb2-associated binder 1 (Gab1) in response to HGF, leading to the enhanced cell motility of human synovial sarcoma cell lines SYO-1, HS-SY-II, and Fuji. (PMID:16849525)
• Bisindolylmaleimide I abolishes the FGF2-mediated association of Shp2 tyrosine phosphatase with Frs2 and Gab1. (PMID:17145761)
• Gab1 is a novel critical regulatory component of endothelial cell migration and capillary formation with a key role in the activation of VEGF-evoked signaling pathways required for angiogenesis (PMID:17178724)
• HGF signaling process from Gab1 to PI3K is negatively regulated by PKC-betaII, and its loss is critical for melanoma cells to gain invasive potential. (PMID:17625596)
• These results suggest that coupling of Grb2 to Gab1 mediates the hepatocyte growth factor-induced strong activation of the ERK pathway, which is required for the inhibition of HepG2 cell proliferation. (PMID:18003605)
• moderate level of Gab1 overexpression stimulated tumor growth (PMID:18192688)
• the Gab1-SHP2-ERK1/2 signaling pathway comprises an inhibitory axis for IGF-I-dependent myogenic differentiation. (PMID:18577518)
• These results underscore the non-redundant and essential roles of Gab1 and Gab2 in endothelial cells, and suggest major contributions of these proteins during in vivo angiogenesis. (PMID:19233262)
• Gab1 couples PI3K-mediated Erythropoietin signals with the Ras/Erk pathway and plays an important role in erythropoietin receptor-mediated signal transduction involved in the proliferation and survival of erythroid cells. (PMID:19665053)
• the phosphorylation of Gab1 by c-Src is important for hepatocyte growth factor -induced DNA synthesis (PMID:19881549)
• The binding of Grb2 adaptor to its downstream partners Sos1 and Gab1 docker is under tight allosteric regulation. (PMID:20005866)
• We could not confirm a major association between Gab1 SNP (rs3805246) and the predisposition to H. pylori infection and CAG in this study populat (PMID:20602450)
• PECAM-1-mediated inhibition of GPVI-dependent platelet responses result from recruitment of SHP-2-p85 complexes to tyrosine-phosphorylated PECAM-1, which diminishes the association of PI3K with activatory signaling molecules Gab1 and LAT (PMID:20723025)
• Gab1 is a critical upstream signaling component in VEGF-induced eNOS activation and tube formation, which is dependent on protein kinase A. (PMID:21282639)
• These data demonstrate that GAB1 is ubiquitinated by CBL and degraded by the proteasome, and plays a role in negative-feedback regulation of HGF/SF-MET signaling. (PMID:21782801)
• Met signals through a cortactin-Gab1 scaffold complex, to mediate invadopodia. (PMID:22366451)
• Data show that bivalent binding drives the formation of the Grb2-Gab1 signaling complex in a noncooperative manner. (PMID:22536782)
• that aberrant Gab1 signaling can directly contribute to breast cancer progression, and that negative feedback sites in docking proteins can be targeted by oncogenic mutations. (PMID:22751113)
• these data underscore the critical roles of Gab1 and Gab2 in IL-22-mediated HaCaT cell proliferation, migration, and differentiation. (PMID:22851227)
• GAB1 plays an important role as part of the mechanism of by which EGFR induces induced activation of the MAPK and AKT pathway. (PMID:22865653)
• an anti-apoptotic role of caspase-cleaved GAB1 in HGF/SF-MET signaling. (PMID:22915589)
• Although Sos1 and Gab1 recognize two non-overlapping sites within the Grb2 adaptor, allostery promotes the formation of two distinct pools of Grb2-Sos1 and Grb2-Gab1 binary signaling complexes in lieu of a composite Sos1-Grb2-Gab1 ternary complex. (PMID:23334917)
• the acquired substrate preference for GAB1 is critical for the ERBB2 mutant-induced oncogenesis. (PMID:23612964)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gab1	ENSDARG00000037018
mus_musculus	Gab1	ENSMUSG00000031714
rattus_norvegicus	Gab1	ENSRNOG00000017879
drosophila_melanogaster	dos	FBGN0016794
caenorhabditis_elegans		WBGENE00004928

Paralogs (7): PHLDB1 (ENSG00000019144), GAB2 (ENSG00000033327), PHLDB2 (ENSG00000144824), PLEKHS1 (ENSG00000148735), GAB3 (ENSG00000160219), PHLDB3 (ENSG00000176531), GAB4 (ENSG00000215568)

Protein

Protein identifiers

GRB2-associated-binding protein 1 — Q13480 (reviewed: Q13480)

Alternative names: GRB2-associated binder 1, Growth factor receptor bound protein 2-associated protein 1

All UniProt accessions (7): Q13480, B7Z3B9, D6RF42, D6RIF8, D6RIS0, H0Y8F4, H0YA71

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that plays a role in intracellular signaling cascades triggered by activated receptor-type kinases. Plays a role in FGFR1 signaling. Probably involved in signaling by the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR). Involved in the MET/HGF-signaling pathway.

Subunit / interactions. Identified in a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1. Forms a tripartite complex containing GAB1, METTL13 and SPRY2. Within the complex interacts with METTL13. Interacts with GRB2 and with other SH2-containing proteins. Interacts with phosphorylated LAT2. Interacts with PTPRJ. Interacts (phosphorylated) with PTPN11. Interacts with HCK.

Post-translational modifications. Phosphorylated in response to FGFR1 activation. Phosphorylated on tyrosine residue(s) by the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR). Tyrosine phosphorylation of GAB1 mediates interaction with several proteins that contain SH2 domains. Phosphorylated on tyrosine residues by HCK upon IL6 signaling.

Disease relevance. Deafness, autosomal recessive, 26 (DFNB26) [MIM:605428] A form of non-syndromic sensorineural deafness characterized by prelingual, severe to profound hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GAB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13480-1	1	yes
Q13480-2	2

RefSeq proteins (2): NP_002030, NP_997006 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR046355	Gab1-4-like	Family

Pfam: PF00169

UniProt features (38 total): modified residue 14, compositionally biased region 7, region of interest 6, sequence variant 5, sequence conflict 2, initiator methionine 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9EIK	X-RAY DIFFRACTION	1.25
9EHD	X-RAY DIFFRACTION	1.59
9QA5	X-RAY DIFFRACTION	2.08
4QSY	X-RAY DIFFRACTION	2.1
9QCD	ELECTRON CRYSTALLOGRAPHY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13480-F1	53.30	0.09

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 (14): 2, 251, 253, 266, 304, 387, 402, 454, 627, 638, 651, 659, 683, 547

Function

Pathways and Gene Ontology

Reactome pathways

25 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-180292	GAB1 signalosome
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5637810	Constitutive Signaling by EGFRvIII
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654710	PI-3K cascade:FGFR3
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5655253	Signaling by FGFR2 in disease
R-HSA-5655291	Signaling by FGFR4 in disease
R-HSA-5655302	Signaling by FGFR1 in disease
R-HSA-5655332	Signaling by FGFR3 in disease
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8851907	MET activates PI3K/AKT signaling
R-HSA-8853659	RET signaling
R-HSA-8865999	MET activates PTPN11
R-HSA-8875555	MET activates RAP1 and RAC1
R-HSA-8875656	MET receptor recycling
R-HSA-9027276	Erythropoietin activates Phosphoinositide-3-kinase (PI3K)
R-HSA-9028335	Activated NTRK2 signals through PI3K
R-HSA-9664565	Signaling by ERBB2 KD Mutants
R-HSA-9665348	Signaling by ERBB2 ECD mutants

MSigDB gene sets: 394 (showing top): PID_SHP2_PATHWAY, GCACCTT_MIR18A_MIR18B, TGGTGCT_MIR29A_MIR29B_MIR29C, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, ZHAN_MULTIPLE_MYELOMA_PR_DN, REACTOME_GAB1_SIGNALOSOME, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, REACTOME_SIGNALING_BY_FGFR, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (12): angiogenesis (GO:0001525), signal transduction (GO:0007165), epidermal growth factor receptor signaling pathway (GO:0007173), insulin receptor signaling pathway (GO:0008286), intracellular signal transduction (GO:0035556), endothelial cell chemotaxis (GO:0035767), vascular endothelial growth factor signaling pathway (GO:0038084), vasodilation (GO:0042311), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of angiogenesis (GO:0045766), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to mechanical stimulus (GO:0071260)

GO Molecular Function (2): signaling adaptor activity (GO:0035591), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), cell-cell junction (GO:0005911)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signaling by FGFR in disease	4
Signaling by MET	2
IRS-mediated signalling	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Intracellular signaling by second messengers	1
Signaling by EGFR	1
Signaling by ERBB2	1
PI3K/AKT Signaling in Cancer	1
Signaling by EGFRvIII in Cancer	1
Downstream signaling of activated FGFR1	1
Downstream signaling of activated FGFR2	1
Downstream signaling of activated FGFR3	1
Downstream signaling of activated FGFR4	1
Negative regulation of the PI3K/AKT network	1
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor protein tyrosine kinase signaling pathway	2
intracellular anatomical structure	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ERBB signaling pathway	1
cellular response to insulin stimulus	1
signal transduction	1
endothelial cell migration	1
cell chemotaxis	1
cellular response to vascular endothelial growth factor stimulus	1
blood vessel diameter maintenance	1
positive regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
protein-macromolecule adaptor activity	1
binding	1
cytoplasm	1
anchoring junction	1

Protein interactions and networks

STRING

1269 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAB1	GRB2	P29354	992
GAB1	PTPN11	Q06124	992
GAB1	EGFR	P00533	986
GAB1	FRS2	Q8WU20	911
GAB1	SHC1	P29353	901
GAB1	SOS1	Q07889	860
GAB1	SRC	P12931	789
GAB1	SOS2	Q07890	782
GAB1	HGF	P14210	754
GAB1	EGF	P01133	720
GAB1	MET	P08581	710
GAB1	CRK	P46108	665
GAB1	CRKL	P46109	606
GAB1	STAT3	P40763	588
GAB1	NTRK1	P04629	580

IntAct

445 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
EGFR	SHC1	psi-mi:“MI:0914”(association)	0.980
PTPN11	GAB1	psi-mi:“MI:0915”(physical association)	0.960
GAB1	PTPN11	psi-mi:“MI:0915”(physical association)	0.960
PTPN11	GAB1	psi-mi:“MI:0914”(association)	0.960
PTPN11	GAB1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.960
PTPN11	GAB1	psi-mi:“MI:0407”(direct interaction)	0.960
GRB2	GAB1	psi-mi:“MI:0915”(physical association)	0.930
GAB1	GRB2	psi-mi:“MI:0915”(physical association)	0.930

BioGRID (268): GTF2A1L (Two-hybrid), GAB1 (Two-hybrid), GAB1 (Affinity Capture-MS), GAB1 (Affinity Capture-MS), GAB1 (Affinity Capture-MS), GAB1 (Proximity Label-MS), CRKL (Co-localization), GAB1 (PCA), GAB1 (PCA), GAB1 (Affinity Capture-Western), PTPN11 (Affinity Capture-Western), FRS2 (Affinity Capture-Western), GAB1 (Proximity Label-MS), GAB1 (Proximity Label-MS), GAB1 (Affinity Capture-MS)

ESM2 similar proteins: A5PMU4, A6QLU3, O89032, P35568, P35569, P35570, P81122, P84770, Q06649, Q13094, Q13191, Q13480, Q13625, Q1LY51, Q1LYG0, Q28224, Q3TTA7, Q4KM52, Q5NBX1, Q5RJW5, Q5TCZ1, Q60787, Q62415, Q6DFR2, Q6GQL0, Q6P4Y6, Q6ZNC4, Q80UZ0, Q8BM65, Q8BSM5, Q8C180, Q8CG79, Q8IVF5, Q8TEW8, Q8WU20, Q8WV28, Q8WWW8, Q91615, Q93073, Q96KQ4

Diamond homologs: A6QLU3, Q00IB7, Q13480, Q2WGN9, Q86SQ0, Q8BUL6, Q8K1N2, Q8WWW8, Q99PF6, Q9EQH1, Q9HB21, Q9QYY0, Q9ULM0, Q9UQC2, Q9VZZ9, Q9W5D0, Q9Z1S8, A1CYS1, A2QNQ5, O08967, P09851, P20936, P42331, P47808, P50904, P54644, Q0CKU4, Q15057, Q3ZBA3, Q4WID6, Q54KA7, Q552C1, Q559T8, Q55GV3, Q5B4C9, Q5FVC7, Q5ZK62, Q6IVG4, Q6ZQK5, Q76MY7

SIGNOR signaling

53 interactions.

A	Effect	B	Mechanism
GAB1	up-regulates	ARHGAP32	relocalization
ERK1/2	“up-regulates activity”	GAB1	phosphorylation
GRB2	up-regulates	GAB1	binding
PTPN11	down-regulates	GAB1	dephosphorylation
PTPN11	“down-regulates activity”	GAB1	dephosphorylation
SRC	“up-regulates activity”	GAB1	phosphorylation
SRC	up-regulates	GAB1	phosphorylation
EGFR	up-regulates	GAB1	phosphorylation
EGFR	“up-regulates activity”	GAB1	phosphorylation
MET	“up-regulates activity”	GAB1	phosphorylation
GAB1	up-regulates	PI3K	binding
PTPN1	“down-regulates activity”	GAB1	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 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
Regulation of signaling by CBL	12	61.4×	2e-17
Downstream signal transduction	14	54.9×	3e-19
Activation of BAD and translocation to mitochondria	7	54.9×	5e-10
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	10	53.5×	5e-14
DAP12 signaling	14	53.2×	3e-19
Constitutive Signaling by EGFRvIII	7	51.5×	8e-10
Role of LAT2/NTAL/LAB on calcium mobilization	8	49.6×	5e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	48.5×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
Fc-epsilon receptor signaling pathway	9	62.2×	2e-12
Fc-gamma receptor signaling pathway involved in phagocytosis	7	46.4×	1e-08
B cell receptor signaling pathway	11	41.6×	4e-13
peptidyl-tyrosine phosphorylation	10	39.8×	8e-12
ephrin receptor signaling pathway	12	38.9×	7e-14
phosphatidylinositol-mediated signaling	5	33.1×	2e-05
positive regulation of Rac protein signal transduction	5	30.6×	2e-05
leukocyte migration	5	29.4×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	79
Likely benign	7
Benign	18

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
545492	NM_002039.4(GAB1):c.347G>A (p.Gly116Glu)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4578 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:143337216:G:A	G10R	1.000
4:143337216:G:C	G10R	1.000
4:143337217:G:A	G10E	1.000
4:143337217:G:T	G10V	1.000
4:143337219:T:A	W11R	1.000
4:143337219:T:C	W11R	1.000
4:143337220:G:C	W11S	1.000
4:143337221:G:C	W11C	1.000
4:143337221:G:T	W11C	1.000
4:143337223:T:A	L12H	1.000
4:143337223:T:C	L12P	1.000
4:143337223:T:G	L12R	1.000
4:143337228:A:C	K14Q	1.000
4:143337228:A:G	K14E	1.000
4:143337229:A:T	K14M	1.000
4:143337230:G:C	K14N	1.000
4:143337230:G:T	K14N	1.000
4:143337232:C:T	S15F	1.000
4:143337234:C:A	P16T	1.000
4:143337234:C:T	P16S	1.000
4:143337235:C:A	P16H	1.000
4:143337238:C:A	P17Q	1.000
4:143337250:T:C	L21S	1.000
4:143415480:T:A	W26R	1.000
4:143415480:T:C	W26R	1.000
4:143415481:G:C	W26S	1.000
4:143415481:G:T	W26L	1.000
4:143415482:G:C	W26C	1.000
4:143415482:G:T	W26C	1.000
4:143415483:A:G	K27E	1.000

dbSNP variants (sampled 300 via entrez): RS1000075588 (4:143337548 T>C), RS1000083913 (4:143363200 T>C), RS1000093145 (4:143474764 A>C,G), RS1000105681 (4:143458959 T>G), RS1000106472 (4:143385885 A>G), RS1000137919 (4:143363512 G>A), RS1000141776 (4:143424505 G>A,T), RS1000162418 (4:143336954 G>A), RS1000192952 (4:143347232 A>G), RS1000212626 (4:143337095 T>C,G), RS1000235300 (4:143452017 G>A,T), RS1000256024 (4:143449447 G>A), RS1000313872 (4:143393894 A>C,G), RS1000320416 (4:143356142 A>G), RS1000360772 (4:143394127 A>G)

Disease associations

OMIM: gene MIM:604439 | disease phenotypes: MIM:616898, MIM:605428

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 26	Limited	Unknown

Mondo (2): 15q14 microdeletion syndrome (MONDO:0014822), autosomal recessive nonsyndromic hearing loss 26 (MONDO:0011553)

Orphanet (2): Cleft palate-congenital heart defect-intellectual disability syndrome due to 15q14 microdeletion (Orphanet:261190), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565329	Deafness, Autosomal Recessive 26 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523286 (SINGLE PROTEIN)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 11 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.17	Kd	680	nM	CHEMBL1685056
6.05	Kd	900	nM	CHEMBL1685055
5.88	Kd	1330	nM	CHEMBL595583
5.68	Kd	2100	nM	CHEMBL4576057
5.66	Kd	2200	nM	CHEMBL4590344
5.57	Kd	2700	nM	CHEMBL1572640
5.55	Kd	2800	nM	CHEMBL1685066
5.03	Ki	9380	nM	CHEMBL4533777

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
coumarin	decreases phosphorylation	1
N-benzyloxycarbonylprolylprolinal	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NVP-TAE684	decreases phosphorylation, decreases reaction, decreases response to substance, increases reaction	1
NSC 689534	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4482511	Binding	Binding affinity to recombinant human GAB1 PH domain expressed in Escherichia coli BL21 (DE3) by surface plasmon resonance assay	Inhibitors of grb2-associated binding protein 1 (gab1) and methods of treating cancer using the same

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7XG	Abcam Raji GAB1 KO	Cancer cell line	Male
CVCL_B9Y5	Abcam THP-1 GAB1 KO	Cancer cell line	Male
CVCL_C6ZZ	Abcam PC-3 GAB1 KO	Cancer cell line	Male
CVCL_SP31	HAP1 GAB1 (-) 1	Cancer cell line	Male
CVCL_XP02	HAP1 GAB1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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