GAB2

Summary

GAB2 (GRB2 associated binding protein 2, HGNC:14458) is a protein-coding gene on chromosome 11q14.1, encoding GRB2-associated-binding protein 2 (Q9UQC2). Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways.

This gene is a member of the GRB2-associated binding protein (GAB) gene family. These proteins contain pleckstrin homology (PH) domain, and bind SHP2 tyrosine phosphatase and GRB2 adapter protein. They act as adapters for transmitting various signals in response to stimuli through cytokine and growth factor receptors, and T- and B-cell antigen receptors. The protein encoded by this gene is the principal activator of phosphatidylinositol-3 kinase in response to activation of the high affinity IgE receptor. Two alternatively spliced transcripts encoding different isoforms have been described for this gene.

Source: NCBI Gene 9846 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 115 total — 1 pathogenic
• MANE Select transcript: NM_080491

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14458
Approved symbol	GAB2
Name	GRB2 associated binding protein 2
Location	11q14.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0571
Ensembl gene	ENSG00000033327
Ensembl biotype	protein_coding
OMIM	606203
Entrez	9846

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000340149, ENST00000361507, ENST00000526030, ENST00000528329, ENST00000528886, ENST00000530915, ENST00000534823

RefSeq mRNA: 2 — MANE Select: NM_080491 NM_012296, NM_080491

CCDS: CCDS8259, CCDS8260

Canonical transcript exons

ENST00000361507 — 10 exons

Exon	Start	End
ENSE00000797737	78220319	78220444
ENSE00001103571	78250157	78250400
ENSE00001103580	78225108	78225202
ENSE00001103583	78222105	78222195
ENSE00001103588	78223412	78223676
ENSE00001103592	78226465	78227051
ENSE00001103593	78221677	78221779
ENSE00002145206	78417646	78417820
ENSE00003491186	78280601	78280901
ENSE00003844502	78215293	78219415

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 97.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.9052 / max 1070.1960, expressed in 1750 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121498	19.2157	1745
121499	0.2586	132
121497	0.1679	89
121484	0.1171	50
206398	0.0810	22
121485	0.0649	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	97.47	gold quality
subthalamic nucleus	UBERON:0001906	96.31	gold quality
medulla oblongata	UBERON:0001896	96.24	gold quality
superior vestibular nucleus	UBERON:0007227	96.05	gold quality
corpus callosum	UBERON:0002336	95.69	gold quality
lateral globus pallidus	UBERON:0002476	95.40	gold quality
ventral tegmental area	UBERON:0002691	95.01	gold quality
spinal cord	UBERON:0002240	94.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.65	gold quality
substantia nigra pars compacta	UBERON:0001965	94.46	gold quality
globus pallidus	UBERON:0001875	94.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.35	gold quality
dorsal plus ventral thalamus	UBERON:0001897	94.33	gold quality
medial globus pallidus	UBERON:0002477	93.88	gold quality
pons	UBERON:0000988	93.82	gold quality
inferior olivary complex	UBERON:0002127	93.78	gold quality
midbrain	UBERON:0001891	93.69	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.65	gold quality
saphenous vein	UBERON:0007318	93.65	gold quality
substantia nigra	UBERON:0002038	93.49	gold quality
amygdala	UBERON:0001876	93.03	gold quality
blood	UBERON:0000178	92.99	gold quality
cervix squamous epithelium	UBERON:0006922	92.25	silver quality
cortical plate	UBERON:0005343	92.19	gold quality
putamen	UBERON:0001874	91.51	gold quality
cranial nerve II	UBERON:0000941	91.33	gold quality
Ammon’s horn	UBERON:0001954	91.31	gold quality
blood vessel layer	UBERON:0004797	91.21	gold quality
hypothalamus	UBERON:0001898	91.17	gold quality
synovial joint	UBERON:0002217	90.86	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.35
E-HCAD-35	yes	11.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, FOS, JUN, NR0B2

miRNA regulators (miRDB)

201 targeting GAB2, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4492	99.87	68.25	3611

Literature-anchored findings (GeneRIF, showing 40)

• comparative FISH mapping of Gab1 and Gab2 genes in human, mouse and rat (PMID:11701952)
• GAB2 is the limiting component of the GAB2-SHP2 complex, signaling Erk MAP kinase activation and terminal differentiation of K562 CML cells. (PMID:11830491)
• The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer. (PMID:12140767)
• over-expression of GRB2 and FLICE2 in RA synovium is caused by TNF-alpha inducibility differentially regulated in RA synoviocytes and provide potential pathogenic roles of these genes in the hyperplasia of the RA synovium. (PMID:14687710)
• Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells. (PMID:15010462)
• Serine residue 623 of Gab2 is a phosphorylation target for MAP kinase (ERK), with demonstrated biochemical consequences on activation of ERK itself and on activation of STAT5. (PMID:15356145)
• We show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts. (PMID:15750601)
• 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)
• role for Gab2 in mammary tumorigenesis (PMID:16253990)
• GAB2 may play a role in development of breast cancer (PMID:16369543)
• GAB2 is a novel target of 11q amplification in acute myeloid leukemia and myelodysplastic syndrome. (PMID:16736498)
• Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer’s neuropathology. (PMID:17553421)
• While Gab2 co-operates with overexpressed c-Src to enhance proliferative signaling, co-expression of Gab2 with activated Src mutants promotes acinar disruption. (PMID:17998934)
• Lyn activation is BCR-ABL independent, it is complexed with the Gab2 and c-Cbl adapter/scaffold proteins, and it mediates persistent Gab2 and BCR-ABL tyrosine phosphorylation in the presence or absence of imatinib. (PMID:18235045)
• The GAB2 gene is at best a minor genetic determinant of AD. (PMID:18272374)
• In an ovarian carcinoma cohort, RSF1 was amplified in 16% of the cases. It was correlated with serous histology. The 11q13 amplicon in ovarian cancer is likely driven by a cassette of genes rather than by a single oncogene. (PMID:18314909)
• These results identify a novel signaling pathway involving Jak2-dependent Gab2 phosphorylation leading to Erk1/2 activation and cell proliferation in response to granulocyte colony-stimulating factor. (PMID:18644434)
• activation of PI3K by c-Kit is dependent both on the direct PI3K-binding site in c-Kit and on the phosphorylation of Gab2. (PMID:18697750)
• These data independently replicate an association between GAB2 and late-onset Alzheimer dementia, which appears to be limited to APOE epsilon4 carriers. (PMID:18853460)
• Results show that GAB2 may not be a disease susceptibility gene for LOAD in Japanese. (PMID:18854865)
• This study found GAB2 to be associated with Alzheimer’s disease. Furthermore, the meta-analysis also suggests that GAB2 modifies the risk of Alzheimer’s disease in APOEepsilon4 carriers. (PMID:19118819)
• model where signal attenuation occurs because 14-3-3 promotes dissociation of Gab2 from Grb2, and thereby uncouples Gab2 from the receptor complex (PMID:19172738)
• GAB2 contains genetic variants that may lead to a modest change in the risk for Alzheimer disease. (PMID:19204163)
• 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)
• GAB2 gene has been proposed as a modifying factor of APOE epsilon 4 allele in Alzheimer’s disease (PMID:19262956)
• possible role of GAB2 as an independent risk factor for Alzheimer’s disease (PMID:19276544)
• These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis (PMID:19342374)
• GAB2 amplification is critical for melanomas arising from sun-protected sites. (PMID:19509136)
• Distinct binding modes of two epitopes in GAB2 that interact with the SH3C domain of GRB2 are reported. (PMID:19523899)
• a pivotal role for GAB2 and its transcriptional targets in anchorage-independent growth and breast cancer metastatic progression. (PMID:19838208)
• Our studies implicate focal amplification of GAB2 in breast carcinogenesis (PMID:19881546)
• Our study does not find any association between the two tested SNPs and GAB2 haplotypes and risk for late-onset Alzheimer disease or any synergetic interaction between the SNPs and ApoE either. (PMID:19924507)
• findings indicate that while Gab2 expression is not prognostic in breast cancer, its role in early disease evolution warrants further analysis (PMID:20087860)
• GAB2 rs2373115 polymorphism was not a remarkable factor in developing Alzheimer disease among Mongolian. (PMID:20188796)
• this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset Alzheimer’s disease in APOEepsilon4 carriers (PMID:20888920)
• The findings implicate GAB2 as a susceptibility gene for late-onset Alzheimer disease in Han Chinese. (PMID:21108942)
• Gab2 regulates cytoskeletal organization and cell motility by regulating RhoA activation and binding to Shp2. (PMID:21118992)
• Our findings implicate an association between genetic variations of GAB2 and Alzheimer disease in Han Chinese (PMID:21285854)
• over-expressed in malignant lung tissues (PMID:21552417)
• Both phosphatidylinositol (PI)-3 kinase and SH2 domain-containing protein tyrosine phosphatase (SHP)2 binding sites of Gab2 are required for mast cell degranulation and the anaphylaxis response. (PMID:21653832)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gab2	ENSDARG00000105120
mus_musculus	Gab2	ENSMUSG00000004508
rattus_norvegicus	Gab2	ENSRNOG00000011882
drosophila_melanogaster	dos	FBGN0016794
caenorhabditis_elegans		WBGENE00004928

Paralogs (7): PHLDB1 (ENSG00000019144), GAB1 (ENSG00000109458), PHLDB2 (ENSG00000144824), PLEKHS1 (ENSG00000148735), GAB3 (ENSG00000160219), PHLDB3 (ENSG00000176531), GAB4 (ENSG00000215568)

Protein

Protein identifiers

GRB2-associated-binding protein 2 — Q9UQC2 (reviewed: Q9UQC2)

Alternative names: GRB2-associated binder 2, Growth factor receptor bound protein 2-associated protein 2, pp100

All UniProt accessions (3): E9PJ26, E9PJE2, Q9UQC2

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways. Regulates osteoclast differentiation mediating the TNFRSF11A/RANK signaling. In allergic response, it plays a role in mast cells activation and degranulation through PI-3-kinase regulation. Also involved in the regulation of cell proliferation and hematopoiesis.

Subunit / interactions. Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, GAB2, TEC and BTK; complex formation increases in the presence of TNFSF11/RANKL. Interacts with SHC1; may mediate interaction with receptors. Interacts with SYK. Interacts with PI-3 kinase. Interacts with GRB2 (via SH3 2 domain). Interacts (phosphorylated) with PTPN11. Interacts with TNFRSF11A (via cytoplasmic domain). Interacts (phosphorylated) with 14-3-3 family proteins SFN, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; prevents interaction with GRB2 and attenuates GAB2 signaling. Interacts with HCK.

Subcellular location. Cytoplasm. Cell membrane. Membrane raft.

Post-translational modifications. Phosphorylated on tyrosine residue(s) by the thrombopoietin receptor (TPOR), stem cell factor receptor (SCFR), and T-cell and B-cell antigen receptors, gp130, IL-2R and IL-3R. Phosphorylated upon stimulation of TNFRSF11A/RANK by TNFSF11/RANKL. Phosphorylated upon EGF stimulation. Phosphorylated on tyrosine residues by HCK upon IL6 signaling. Dephosphorylated by PTPN11.

Domain organisation. The SH3-binding motifs mediate interaction with SHC1 and GRB2. The PH domain mediates phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate binding.

Similarity. Belongs to the GAB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UQC2-1	1	yes
Q9UQC2-2	2

RefSeq proteins (2): NP_036428, NP_536739* (*=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 (53 total): modified residue 33, compositionally biased region 5, region of interest 5, sequence variant 2, mutagenesis site 2, short sequence motif 2, chain 1, domain 1, splice variant 1, helix 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
6Y3R	X-RAY DIFFRACTION	1.5
2VWF	X-RAY DIFFRACTION	1.58
2W0Z	X-RAY DIFFRACTION	1.7
5EXA	X-RAY DIFFRACTION	1.95
6Y3S	X-RAY DIFFRACTION	1.95
5EWZ	X-RAY DIFFRACTION	2.34
6ZVD	X-RAY DIFFRACTION	2.5
6ZVB	X-RAY DIFFRACTION	2.51
6ZVC	X-RAY DIFFRACTION	2.51
6ZVE	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQC2-F1	52.73	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.

Post-translational modifications (33): 2, 133, 140, 141, 148, 149, 159, 164, 210, 218, 223, 264, 265, 266, 278, 281, 285, 287, 293, 331 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
210	impaired interaction with 14-3-3 proteins and increased egf-independent cell proliferation; when associated with a-391.
391	impaired interaction with 14-3-3 proteins and increased egf-independent cell proliferation; when associated with a-210.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1839117	Signaling by cytosolic FGFR1 fusion mutants
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2730905	Role of LAT2/NTAL/LAB on calcium mobilization
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8853659	RET signaling
R-HSA-8983432	Interleukin-15 signaling
R-HSA-912526	Interleukin receptor SHC signaling
R-HSA-9607240	FLT3 Signaling
R-HSA-9645135	STAT5 Activation
R-HSA-9674555	Signaling by CSF3 (G-CSF)
R-HSA-9680350	Signaling by CSF1 (M-CSF) in myeloid cells
R-HSA-9702518	STAT5 activation downstream of FLT3 ITD mutants
R-HSA-9703465	Signaling by FLT3 fusion proteins
R-HSA-9703648	Signaling by FLT3 ITD and TKD mutants

MSigDB gene sets: 0 (showing top):

GO Biological Process (6): signal transduction (GO:0007165), positive regulation of cell population proliferation (GO:0008284), osteoclast differentiation (GO:0030316), positive regulation of mast cell degranulation (GO:0043306), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169)

GO Molecular Function (4): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Cytokine Signaling in Immune system	3
Interleukin-2 family signaling	2
FLT3 signaling in disease	2
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
Signaling by Receptor Tyrosine Kinases	1
FGFR1 mutant receptor activation	1
PI3K/AKT Signaling in Cancer	1
Fc epsilon receptor (FCERI) signaling	1
Negative regulation of the PI3K/AKT network	1
Axon guidance	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
FLT3 Signaling	1
Signaling by FLT3 ITD and TKD mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
myeloid leukocyte differentiation	1
positive regulation of leukocyte degranulation	1
mast cell degranulation	1
regulation of mast cell degranulation	1
intracellular signaling cassette	1
enzyme-linked receptor protein signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
signaling receptor complex adaptor activity	1
receptor tyrosine kinase binding	1
anion binding	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
membrane microdomain	1

Protein interactions and networks

STRING

848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAB2	GRB2	P29354	996
GAB2	PTPN11	Q06124	995
GAB2	SHC1	P29353	954
GAB2	GZMB	P10144	947
GAB2	SOS1	Q07889	922
GAB2	SOS2	Q07890	915
GAB2	A1BG	P04217	856
GAB2	ABL1	P00519	852
GAB2	STAT5B	P51692	793
GAB2	PIK3R1	P27986	780
GAB2	SRC	P12931	772
GAB2	SYK	P43405	766
GAB2	FYN	P06241	762
GAB2	APOE	P02649	719
GAB2	MST1R	Q04912	704
GAB2	LYN	P07948	704

IntAct

146 interactions, top by confidence:

A	B	Type	Score
GAB2	GRB2	psi-mi:“MI:0915”(physical association)	0.960
GRB2	GAB2	psi-mi:“MI:0915”(physical association)	0.960
GAB2	GRB2	psi-mi:“MI:0914”(association)	0.960
GRAP2	STAMBP	psi-mi:“MI:0914”(association)	0.810
PIK3R3	PIK3CD	psi-mi:“MI:0914”(association)	0.800
GAB2	YWHAB	psi-mi:“MI:0915”(physical association)	0.790
YWHAB	GAB2	psi-mi:“MI:0914”(association)	0.790
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
PTPN11	GAB2	psi-mi:“MI:0914”(association)	0.730
EGFR	GAB2	psi-mi:“MI:0915”(physical association)	0.670
GRAP2	GAB2	psi-mi:“MI:0915”(physical association)	0.670
GAB2	EGFR	psi-mi:“MI:0914”(association)	0.670
GAB2	SHC1	psi-mi:“MI:0915”(physical association)	0.660
GAB2	SHC1	psi-mi:“MI:0407”(direct interaction)	0.660
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
MYO15B	GAB2	psi-mi:“MI:0915”(physical association)	0.560
GAB2	ACP2	psi-mi:“MI:0915”(physical association)	0.560
RPSA	GAB2	psi-mi:“MI:0915”(physical association)	0.560
RFFL	GAB2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (195): GAB2 (Two-hybrid), GAB2 (Affinity Capture-MS), GAB2 (Affinity Capture-MS), GAB2 (Affinity Capture-MS), FRS2 (Affinity Capture-Western), GAB2 (Affinity Capture-MS), GAB2 (Affinity Capture-MS), GAB2 (Affinity Capture-MS), KCTD3 (Affinity Capture-MS), KIF13B (Affinity Capture-MS), ZBTB21 (Affinity Capture-MS), GAB2 (Affinity Capture-MS), GIGYF1 (Affinity Capture-MS), LRFN1 (Affinity Capture-MS), DENND1A (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

14 interactions.

A	Effect	B	Mechanism
GAB2	up-regulates	ARHGAP32	relocalization
ZAP70	“up-regulates activity”	GAB2	phosphorylation
AKT	down-regulates	GAB2	phosphorylation
PTPN11	down-regulates	GAB2	dephosphorylation
MAPK1	up-regulates	GAB2	phosphorylation
MAPK3	up-regulates	GAB2	phosphorylation
JAK2	up-regulates	GAB2	phosphorylation
GAB2	up-regulates	PIK3CA	binding
GRB2	up-regulates	GAB2	binding
AKT1	down-regulates	GAB2	phosphorylation
GAB2	up-regulates	PI3K	binding
Gbeta	up-regulates	GAB2	phosphorylation
ERK1/2	up-regulates	GAB2	phosphorylation
FYN	“up-regulates activity”	GAB2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 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
Activation of BAD and translocation to mitochondria	7	73.0×	6e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	64.4×	8e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	64.4×	8e-10
Activation of BH3-only proteins	7	47.6×	6e-09
Tie2 Signaling	5	41.2×	3e-06
Interleukin-3, Interleukin-5 and GM-CSF signaling	8	34.8×	5e-09
Regulation of signaling by CBL	5	34.0×	6e-06
Interleukin receptor SHC signaling	6	33.5×	7e-07

GO biological processes:

GO term	Partners	Fold	FDR
insulin-like growth factor receptor signaling pathway	5	27.2×	3e-04
protein targeting	6	24.1×	7e-05
insulin receptor signaling pathway	7	17.1×	7e-05
epidermal growth factor receptor signaling pathway	6	16.3×	4e-04
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	13.9×	6e-04
B cell differentiation	5	12.0×	5e-03
Ras protein signal transduction	5	11.3×	6e-03
cellular response to insulin stimulus	6	11.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	97
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
441903	GRCh37/hg19 11p15.5-q25(chr11:230616-134938470)x3	Pathogenic

SpliceAI

2714 predictions. Top by Δscore:

Variant	Effect	Δscore
11:78219246:T:TA	donor_gain	1.0000
11:78219413:TGG:T	acceptor_gain	1.0000
11:78221672:CTCA:C	donor_loss	1.0000
11:78221673:TCACC:T	donor_loss	1.0000
11:78221674:CACC:C	donor_loss	1.0000
11:78221775:TGTGG:T	acceptor_gain	1.0000
11:78221776:GTGG:G	acceptor_gain	1.0000
11:78221777:TGG:T	acceptor_gain	1.0000
11:78221778:GG:G	acceptor_gain	1.0000
11:78221779:GC:G	acceptor_loss	1.0000
11:78221780:C:CC	acceptor_gain	1.0000
11:78221780:C:CG	acceptor_loss	1.0000
11:78221783:T:C	acceptor_gain	1.0000
11:78221783:T:TC	acceptor_gain	1.0000
11:78222096:CGCA:C	donor_gain	1.0000
11:78222099:A:AC	donor_gain	1.0000
11:78222100:C:CC	donor_gain	1.0000
11:78222100:CTTA:C	donor_gain	1.0000
11:78222101:TTACT:T	donor_loss	1.0000
11:78222102:TA:T	donor_loss	1.0000
11:78222103:A:AC	donor_gain	1.0000
11:78222103:A:C	donor_loss	1.0000
11:78222104:C:CA	donor_gain	1.0000
11:78222104:CTTGG:C	donor_gain	1.0000
11:78222191:CTTTG:C	acceptor_gain	1.0000
11:78222192:TTTG:T	acceptor_gain	1.0000
11:78222193:TTG:T	acceptor_gain	1.0000
11:78222194:TG:T	acceptor_gain	1.0000
11:78222196:C:CA	acceptor_loss	1.0000
11:78222196:C:CC	acceptor_gain	1.0000

AlphaMissense

4466 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:78219342:A:G	L654P	1.000
11:78219372:A:T	V644D	1.000
11:78223436:G:T	R515S	1.000
11:78280624:A:G	F118S	1.000
11:78280629:A:C	C116W	1.000
11:78280630:C:T	C116Y	1.000
11:78280631:A:G	C116R	1.000
11:78280651:A:T	V109D	1.000
11:78280653:C:A	W108C	1.000
11:78280653:C:G	W108C	1.000
11:78280654:C:G	W108S	1.000
11:78280655:A:G	W108R	1.000
11:78280655:A:T	W108R	1.000
11:78280681:G:T	A99D	1.000
11:78280687:A:G	L97P	1.000
11:78280687:A:T	L97Q	1.000
11:78280691:A:C	Y96D	1.000
11:78280692:A:C	F95L	1.000
11:78280692:A:T	F95L	1.000
11:78280694:A:G	F95L	1.000
11:78280699:C:G	R93P	1.000
11:78280700:G:T	R93S	1.000
11:78280719:A:C	F86L	1.000
11:78280719:A:T	F86L	1.000
11:78280720:A:G	F86S	1.000
11:78280721:A:G	F86L	1.000
11:78280779:A:C	C66W	1.000
11:78280780:C:T	C66Y	1.000
11:78280781:A:G	C66R	1.000
11:78280789:A:G	L63P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002574 (11:78339521 A>G), RS1000007730 (11:78255872 A>G), RS1000010387 (11:78241140 C>T), RS1000057505 (11:78356230 T>C,G), RS1000062879 (11:78241381 A>C), RS1000075188 (11:78321154 G>A), RS1000118930 (11:78380461 C>T), RS1000124912 (11:78272412 A>C,T), RS1000134357 (11:78240017 AG>A,AGG), RS1000145139 (11:78276682 T>C,G), RS1000151432 (11:78346495 T>C), RS1000154169 (11:78385531 T>C), RS1000165565 (11:78350602 A>G), RS1000166511 (11:78390816 A>T), RS1000167572 (11:78229964 G>A,T)

Disease associations

OMIM: gene MIM:606203 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST000046_1	Alzheimer’s disease (late onset)	1.000000e-10
GCST000880_18	Menarche (age at onset)	8.000000e-09
GCST002541_88	Menarche (age at onset)	2.000000e-12
GCST002775_5	Alzheimer’s disease (survival time)	3.000000e-06
GCST003246_2	Testicular germ cell tumor	1.000000e-10
GCST004635_21	Testicular germ cell tumor	5.000000e-06
GCST004713_28	Testicular germ cell tumor	6.000000e-06
GCST004904_239	Body mass index	1.000000e-08
GCST005984_56	Glomerular filtration rate	1.000000e-08
GCST005985_35	Creatinine levels	2.000000e-08
GCST006013_4	Lactate dehydrogenase levels	3.000000e-10
GCST006014_19	Creatine kinase levels	1.000000e-14
GCST006075_13	Hair color	6.000000e-44
GCST006412_123	Intraocular pressure	2.000000e-08
GCST006612_53	LDL cholesterol	6.000000e-09
GCST006613_56	Triglycerides	3.000000e-11
GCST006614_29	Total cholesterol levels	1.000000e-14
GCST006627_22	Diastolic blood pressure	4.000000e-10
GCST006667_1	Lipid traits (pleiotropy) (HIPO component 2)	3.000000e-08
GCST006988_48	Blond vs. brown/black hair color	2.000000e-24
GCST006989_12	Brown vs. black hair color	1.000000e-13
GCST007277_15	Tourette syndrome	5.000000e-06
GCST007344_34	Estimated glomerular filtration rate	1.000000e-08
GCST007656_10	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	4.000000e-12
GCST008058_100	Estimated glomerular filtration rate	5.000000e-19
GCST008059_39	Estimated glomerular filtration rate	3.000000e-14
GCST008060_42	Estimated glomerular filtration rate	2.000000e-06
GCST010244_398	Triglyceride levels	2.000000e-10
GCST90002386_357	High light scatter reticulocyte percentage of red cells	9.000000e-10
GCST90002401_189	Platelet distribution width	8.000000e-11

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0000714	survival time
EFO:0004340	body mass index
EFO:0004808	L lactate dehydrogenase measurement
EFO:0004534	creatine kinase measurement
EFO:0004695	intraocular pressure measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0006336	diastolic blood pressure
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0003924	hair color
EFO:0007984	platelet component distribution width
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, decreases methylation, increases methylation	3
Benzo(a)pyrene	decreases expression, increases methylation	3
sodium arsenite	affects expression, increases expression	2
Valproic Acid	increases expression, decreases methylation	2
Cyclosporine	increases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
afimoxifene	increases expression, decreases reaction	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
ferrous chloride	increases expression	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1

Clinical trials (associated diseases)

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