GRB10

Summary

GRB10 (growth factor receptor bound protein 10, HGNC:4564) is a protein-coding gene on chromosome 7p12.1, encoding Growth factor receptor-bound protein 10 (Q13322). Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways.

The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. Overexpression of some isoforms of the encoded protein inhibits tyrosine kinase activity and results in growth suppression. This gene is imprinted in a highly isoform- and tissue-specific manner, with expression observed from the paternal allele in the brain, and from the maternal allele in the placental trophoblasts. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 2887 — RefSeq curated summary.

At a glance

• GWAS associations: 43
• Clinical variants (ClinVar): 108 total
• Phenotypes (HPO): 59
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001350814

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4564
Approved symbol	GRB10
Name	growth factor receptor bound protein 10
Location	7p12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106070
Ensembl biotype	protein_coding
OMIM	601523
Entrez	2887

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 18 protein_coding, 5 retained_intron, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000335866, ENST00000357271, ENST00000398810, ENST00000398812, ENST00000401949, ENST00000402497, ENST00000402578, ENST00000403097, ENST00000406641, ENST00000407526, ENST00000428711, ENST00000439044, ENST00000461886, ENST00000465602, ENST00000467386, ENST00000470992, ENST00000473696, ENST00000482397, ENST00000483819, ENST00000490051, ENST00000492265, ENST00000643299, ENST00000644716, ENST00000644769, ENST00000644879, ENST00000645075, ENST00000876184, ENST00000918859, ENST00000918860

RefSeq mRNA: 8 — MANE Select: NM_001350814 NM_001001549, NM_001001550, NM_001001555, NM_001350814, NM_001350815, NM_001350816, NM_001371008, NM_001371009

CCDS: CCDS43582, CCDS43583, CCDS47586, CCDS87504

Canonical transcript exons

ENST00000401949 — 19 exons

Exon	Start	End
ENSE00000683078	50595437	50595530
ENSE00001407972	50755887	50756056
ENSE00001534990	50780627	50780736
ENSE00001534991	50782424	50782896
ENSE00001551737	50590068	50593098
ENSE00001626202	50618071	50618139
ENSE00001632392	50619170	50619285
ENSE00001654867	50612741	50612839
ENSE00001668857	50606337	50606414
ENSE00001673533	50616210	50616347
ENSE00001695732	50669722	50669863
ENSE00001727478	50626822	50626978
ENSE00001798287	50614770	50614880
ENSE00003573734	50605290	50605406
ENSE00003608488	50703821	50703908
ENSE00003625459	50603998	50604085
ENSE00003661219	50604311	50604377
ENSE00003664117	50732272	50732368
ENSE00003791619	50674436	50674658

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8542 / max 252.0935, expressed in 1613 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84115	6.2170	1508
84112	1.9563	400
84113	0.9887	573
84114	0.5059	264
84111	0.1863	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.39	gold quality
substantia nigra pars compacta	UBERON:0001965	97.48	gold quality
visceral pleura	UBERON:0002401	97.39	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.97	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.93	gold quality
endothelial cell	CL:0000115	96.71	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.63	gold quality
middle temporal gyrus	UBERON:0002771	96.51	gold quality
pancreatic ductal cell	CL:0002079	96.44	gold quality
choroid plexus epithelium	UBERON:0003911	96.13	gold quality
pleura	UBERON:0000977	96.12	gold quality
nephron tubule	UBERON:0001231	96.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.02	gold quality
metanephric glomerulus	UBERON:0004736	95.91	gold quality
parietal pleura	UBERON:0002400	95.86	gold quality
renal glomerulus	UBERON:0000074	95.68	gold quality
pancreas	UBERON:0001264	95.52	gold quality
sperm	CL:0000019	95.35	gold quality
superior vestibular nucleus	UBERON:0007227	95.35	gold quality
inferior olivary complex	UBERON:0002127	95.21	gold quality
kidney epithelium	UBERON:0004819	95.15	gold quality
inferior vagus X ganglion	UBERON:0005363	94.97	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.78	gold quality
medulla oblongata	UBERON:0001896	94.74	gold quality
diaphragm	UBERON:0001103	94.62	gold quality
right atrium auricular region	UBERON:0006631	94.47	gold quality
postcentral gyrus	UBERON:0002581	94.43	gold quality
cardiac atrium	UBERON:0002081	94.37	gold quality
gastrocnemius	UBERON:0001388	94.26	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	34.12
E-GEOD-135922	yes	22.12
E-ANND-3	yes	14.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CRX, CTCF, KLF15, NRL, OTX2, STAT5A, STAT5B, TP63, ZNF239

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 35)

• Role in the regulation of mitogenesis by receptor tyrosine kinases. (PMID:10454568)
• Mostly localized to the mitochondria. Can relocalize to the plasma membrane and lamellipodia under certain conditions. (PMID:10585452)
• role in inhibiting insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor (PMID:12493740)
• The structure of this protein’s SH domains affect ligand specificity. (PMID:12551896)
• Grb10 acts as a positive regulator in VEGF-R2 signaling and protects VEGF-R2 from degradation by interacting with Nedd4, a component of the endocytic machinery (PMID:15060076)
• GRB10 protein products are correlated with parameters of birth size. (PMID:15506681)
• there is a phosphorylation-regulated complex formation of Grb10 with 14-3-3 and Akt (PMID:15722337)
• Up-regulation of growth factor receptor-bound protein 10 is associated with cervical squamous cell carcinoma (PMID:15870923)
• Ser(150) and Ser(476) of human Grb10zeta are phosphorylated in intact cells. (PMID:15952796)
• Together, our results suggest that, in addition to inhibiting IR kinase activity by directly binding to the IR, Grb10 also negatively regulates insulin signaling by mediating insulin-stimulated degradation of the receptor. (PMID:16434550)
• Single nucleotide polymorphism is associated with type 2 diabetes among Whites. (PMID:16644667)
• GRB10 is a novel negative regulator of the Wnt signaling pathway. The finding that GRB10 interferes with the binding of Axin to LRP6 indicated a possible molecular mechanism by which the overexpression of GRB10 suppresses Wnt signaling. (PMID:17376403)
• GRB10 gene is expressed from the paternal allele in the brain, but from the maternal allele in the placental trophoblasts. (PMID:19487367)
• Results illuminate the membrane-recruitment mechanisms of Grb7, Grb10 and Grb14. (PMID:19648926)
• Grb10 interacts with Bim L and inhibits its proapoptotic activity in a phosphorylation-dependant manner. (PMID:20174874)
• discovery of Grb10 as an mTORC1 substrate (PMID:21659604)
• H19 and GRB10 methylation was normal in Albright’s hereditary osteodystrophy patients. (PMID:22679513)
• Studies indicate that insulin receptor (IR) and IGF Type 1 Receptor (IGFR) have been identified as important partners of Grb10/14 and SH2B1/B2 adaptors. (PMID:23190452)
• Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. (PMID:23246379)
• Tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism. (PMID:24699409)
• Association of the intronic polymorphism rs12540874 A>G of the GRB10 gene with high birth weight. (PMID:25103788)
• This study demonstrated that the most significant SNP (rs11770199; p = 0.0003) in single-site analysis was located on chromosome 7 in the GRB10 gene. (PMID:25391383)
• placental expression associated positively with placental weight, birth weight, and neonatal head circumference (PMID:26390806)
• Risk alleles for 6 loci increased glucose levels from birth to 5 years of age (ADCY5, ADRA2A, CDKAL1, CDKN2A/B, GRB10, and TCF7L2 (PMID:27049325)
• Study found FGFR3 gene mutation plus GRB10 gene duplication in a patient with achondroplasia plus growth delay with prenatal onset (PMID:27370225)
• GRB10 may regulate degradation of the IL-4 receptor-signaling complex through interactions with NEDD4.2. (PMID:27742835)
• Data suggest that GRB10 and GRB14 are both Ca2+-dependent CaM-binding proteins; more than one CaM-binding site and/or accessory CaM-binding sites appear to exist in GRB10 and GRB14, as compared to a single one present in GRB7. (GRB10 = growth factor receptor-bound protein 10; GRB14 = growth factor receptor-bound protein 14; CaM = calmodulin; GRB7 = growth factor receptor-bound protein 7) (PMID:28295264)
• Through syngeneic comparison, our study identifies for the first time that Grb10 is associated with the pluripotency state in nuclear transfer embryonic stem cells. (PMID:28476045)
• Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models,we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC. (PMID:29544736)
• results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor-promoting effects in prostate cancer (PMID:30379590)
• inhibition of mTORC1 with rapamycin blocked Grb10 Ser476 phosphorylation and repressed a negative-feedback loop on PI3K/Akt signaling that increased myotube responsiveness to insulin (PMID:31794259)
• GRB10 sustains AR activity by interacting with PP2A in prostate cancer cells. (PMID:33038264)
• Circ_0009910 shuttled by exosomes regulates proliferation, cell cycle and apoptosis of acute myeloid leukemia cells by regulating miR-5195-3p/GRB10 axis. (PMID:33969901)
• GRB10 is a novel factor associated with gastric cancer proliferation and prognosis. (PMID:37179120)
• Binds to the Raf-1 and MEK1 kinases. Potential role in the regulation of apoptosis. (PMID:9553107)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	grb10a	ENSDARG00000002013
danio_rerio	grb10b	ENSDARG00000035308
mus_musculus	Grb10	ENSMUSG00000020176
rattus_norvegicus	Grb10	ENSRNOG00000004290
drosophila_melanogaster	pico	FBGN0261811
caenorhabditis_elegans		WBGENE00003243

Paralogs (4): APBB1IP (ENSG00000077420), GRB14 (ENSG00000115290), GRB7 (ENSG00000141738), RAPH1 (ENSG00000173166)

Protein

Protein identifiers

Growth factor receptor-bound protein 10 — Q13322 (reviewed: Q13322)

Alternative names: GRB10 adapter protein, Insulin receptor-binding protein Grb-IR

All UniProt accessions (5): Q13322, A0A2R8Y6Q4, A0A2R8YCL1, C9JTW6, H7C3B9

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. May play a role in mediating insulin-stimulated ubiquitination of INSR, leading to proteasomal degradation. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2.

Subunit / interactions. Interacts with ligand-activated tyrosine kinase receptors, including FGFR1, INSR, IGF1R, MET and PDGFRB in a phosphotyrosine-dependent manner through the SH2 domain. Poorly binds to the EGFR. Directly interacts with MAP3K14/NIK and is recruited to the EGFR-ERBB2 complex. Interacts with GIGYF1/PERQ1 and GIGYF2/TNRC15. When unphosphorylated, interacts with AKT1 and when phosphorylated with YWHAE/14-3-3 epsilon. Interacts with NEDD4. Interacts with LRP6, thus interfering with the binding of AXIN1 to LRP6. Binds to activated NRAS.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed in fetal and adult tissues, including fetal and postnatal liver, lung, kidney, skeletal muscle, heart, spleen, skin and brain.

Post-translational modifications. Phosphorylated on serine residues upon EGF, FGF and PDGF stimulation. Phosphorylated at Tyr-67 by TEC.

Activity regulation. Phosphorylation by mTORC1 stabilizes and activates GRB10 constituting a feedback pathway by which mTORC1 inhibits INSR-dependent signaling.

Domain organisation. The PH domain binds relatively non-specifically to several phosphoinositides, including PI(5)P, PI(4,5)P2, PI(3,4)P2 and PI(3,4,5)P3, with modest affinities.

Miscellaneous. The GRB10 locus is imprinted. During embryonic development, the expression in the brain and spinal cord is from the paternal allele, while in placental villous trophoblasts and skeletal muscle, it is from the maternal one. Expression is biallelic in most other tissues. Paternal expression in the brain is maintained throughout adulthood. Imprinting often is isoform-specific. GRB10 is unlikely to be responsible for Silver-Russell syndrome (SRS).

Similarity. Belongs to the GRB7/10/14 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q13322-1	3, Zeta	yes
Q13322-2	1, Beta
Q13322-3	2, Gamma, Beta, SV-1
Q13322-4	4, Epsilon

RefSeq proteins (8): NP_001001549, NP_001001550, NP_001001555, NP_001337743, NP_001337744, NP_001337745, NP_001357937, NP_001357938 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000159	RA_dom	Domain
IPR000980	SH2	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015042	BPS-dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035037	Grb10_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR039664	GRB/APBB1IP	Family
IPR039665	PH_APBB1IP	Domain

Pfam: PF00017, PF00169, PF08947, PF21989

UniProt features (72 total): strand 19, mutagenesis site 14, helix 11, modified residue 7, sequence conflict 5, domain 3, splice variant 3, sequence variant 3, region of interest 2, turn 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1NRV	X-RAY DIFFRACTION	1.65
3HK0	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13322-F1	74.68	0.49

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 (7): 150, 418, 428, 431, 476, 67, 104

Mutagenesis-validated functional residues (14):

Position	Phenotype
104	no effect on phosphorylation.
134	no effect on ywhae-binding.
136	no effect on nedd4-binding; when associated with a-139 and a-141.
139	no effect on nedd4-binding; when associated with a-136 and a-141.
141	no effect on nedd4-binding; when associated with a-136 and a-139.
150	loss of phosphorylation.
300	2-fold loss of inositide-binding.
305	5-fold loss of inositide-binding.
308	5-fold loss of inositide-binding.
355	5-fold loss of inositide-binding.
418	no net loss of phosphorylation, this may be due to a compensatory phosphorylation of t-422 in vitro.
428	impairs ywhae-binding.
476	loss of phosphorylation.
520	no effect on nedd4-binding. no effect on the disruption of the interaction between insr and irs1 and irs2.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-74713	IRS activation
R-HSA-74749	Signal attenuation
R-HSA-74751	Insulin receptor signalling cascade
R-HSA-8853659	RET signaling
R-HSA-9607240	FLT3 Signaling
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency

MSigDB gene sets: 494 (showing top): MODULE_92, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, DITTMER_PTHLH_TARGETS_UP, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (14): insulin receptor signaling pathway (GO:0008286), gene expression (GO:0010467), negative regulation of Wnt signaling pathway (GO:0030178), positive regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030949), response to insulin (GO:0032868), positive regulation of phosphorylation (GO:0042327), negative regulation of glycogen biosynthetic process (GO:0045719), negative regulation of D-glucose import across plasma membrane (GO:0046325), negative regulation of insulin receptor signaling pathway (GO:0046627), insulin-like growth factor receptor signaling pathway (GO:0048009), ERK1 and ERK2 cascade (GO:0070371), positive regulation of cold-induced thermogenesis (GO:0120162), vascular associated smooth muscle cell migration (GO:1904738), signal transduction (GO:0007165)

GO Molecular Function (5): insulin receptor binding (GO:0005158), signaling receptor complex adaptor activity (GO:0030159), identical protein binding (GO:0042802), protein binding (GO:0005515), protein-macromolecule adaptor activity (GO:0030674)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Insulin receptor signalling cascade	2
Signaling by Receptor Tyrosine Kinases	1
Signaling by Insulin receptor	1
Axon guidance	1
Cytokine Signaling in Immune system	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor protein tyrosine kinase signaling pathway	2
negative regulation of signal transduction	2
signaling receptor binding	2
protein binding	2
cellular anatomical structure	2
cellular response to insulin stimulus	1
macromolecule biosynthetic process	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
positive regulation of signal transduction	1
regulation of vascular endothelial growth factor receptor signaling pathway	1
vascular endothelial growth factor receptor signaling pathway	1
response to peptide hormone	1
phosphorylation	1
regulation of phosphorylation	1
positive regulation of phosphate metabolic process	1
glycogen biosynthetic process	1
regulation of glycogen biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
negative regulation of glycogen metabolic process	1
negative regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
insulin receptor signaling pathway	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
MAPK cascade	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
smooth muscle cell migration	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signaling adaptor activity	1
binding	1
molecular adaptor activity	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2000 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRB10	IGF1R	P08069	981
GRB10	IGF1	P01343	977
GRB10	GIGYF2	Q6Y7W6	963
GRB10	GIGYF1	O75420	932
GRB10	MEST	Q5EB52	905
GRB10	INS	P01308	890
GRB10	IGF2	P01344	863
GRB10	PLAGL1	Q9UM63	820
GRB10	COBL	O75128	815
GRB10	INSR	P06213	787
GRB10	COPG2	Q9UBF2	775
GRB10	PEG10	Q86TG7	769
GRB10	PEG3	P78418	759
GRB10	NEDD4	P46934	747
GRB10	EGFR	P00533	730

IntAct

60 interactions, top by confidence:

A	B	Type	Score
EGFR	GRB10	psi-mi:“MI:0915”(physical association)	0.730
EGFR	GRB10	psi-mi:“MI:0407”(direct interaction)	0.730
GRB10	EGFR	psi-mi:“MI:0915”(physical association)	0.730
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
GRB10	FLT3	psi-mi:“MI:0915”(physical association)	0.590
FLT3	GRB10	psi-mi:“MI:0915”(physical association)	0.590
INSR	GRB10	psi-mi:“MI:0915”(physical association)	0.580
GRB10	INSR	psi-mi:“MI:0407”(direct interaction)	0.580
GRB10	INSR	psi-mi:“MI:0915”(physical association)	0.580
RCAN3	GRB10	psi-mi:“MI:0915”(physical association)	0.570
GRB10	RCAN3	psi-mi:“MI:0915”(physical association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
GRB10	YWHAE	psi-mi:“MI:0915”(physical association)	0.560
SFN	GRB10	psi-mi:“MI:0915”(physical association)	0.560
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
WDR59	EPB41L2	psi-mi:“MI:0914”(association)	0.530
GRB10	IGF1R	psi-mi:“MI:0915”(physical association)	0.530
GRB10	IGF1R	psi-mi:“MI:0407”(direct interaction)	0.530
GRB10	EPHB1	psi-mi:“MI:0915”(physical association)	0.500
EPHB1	GRB2	psi-mi:“MI:0914”(association)	0.500
GRB10	BAIAP2	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (224): AKT1 (Reconstituted Complex), GRB10 (Biochemical Activity), YWHAE (Reconstituted Complex), YWHAE (Affinity Capture-Western), GRB10 (Affinity Capture-Western), GRB10 (Two-hybrid), GRB10 (Two-hybrid), CHFR (Reconstituted Complex), NARS (Co-fractionation), BAIAP2 (Two-hybrid), RCAN3 (Two-hybrid), GRB10 (Affinity Capture-Luminescence), GRB10 (Affinity Capture-MS), GRB10 (PCA), GRB10 (Affinity Capture-Western)

ESM2 similar proteins: A0A140LI67, B5KFD7, D4A7V9, M0R4F8, O08774, O35827, O43187, O70167, O70173, O88866, O88900, O95398, O95704, P0C5Y8, Q0P5I2, Q13322, Q14449, Q4QQS0, Q5BIW4, Q5ICW4, Q5JV73, Q5PQS0, Q5R810, Q60760, Q68DX3, Q6IFT4, Q6IRN0, Q6P4K6, Q6REY9, Q6S5L8, Q6TXD4, Q7TSI1, Q80TQ5, Q80VA5, Q8BW88, Q8CFA1, Q8IWE5, Q8R1C9, Q8R2S1, Q8VCC8

Diamond homologs: A0A8I3NFE2, A0FI79, A0JNB0, A1Y2K1, A6QLK6, B2RZ59, B5KFD7, D3ZGS3, D7PF45, F1RDG9, G5ECJ6, O14306, O14796, O15357, O35324, O60880, O88890, O88900, P00519, P00520, P00521, P00522, P03949, P06239, P06241, P09851, P0CE43, P10447, P17713, P20936, P29350, P29351, P32019, P34370, P39688, P42684, P42685, P42686, P50904, P53356

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
14-3-3	up-regulates	GRB10	binding
MAPK1	up-regulates	GRB10	phosphorylation
MAPK3	up-regulates	GRB10	phosphorylation
GRB10	down-regulates	IGF1R	binding
GRB10	down-regulates	INSR	binding
MTOR	up-regulates	GRB10	phosphorylation
mTORC1	up-regulates	GRB10	phosphorylation
Gbeta	up-regulates	GRB10	phosphorylation
ERK1/2	up-regulates	GRB10	phosphorylation
RET	up-regulates	GRB10	binding
FYN	down-regulates	GRB10	phosphorylation
SRC	down-regulates	GRB10	phosphorylation
GRB10	“up-regulates activity”	PIK3R1	binding
GRB10	“up-regulates activity”	PI3K	binding
FLT3	“up-regulates activity”	GRB10	binding
GIGYF2	“up-regulates activity”	GRB10	binding
MAPK1	unknown	GRB10	phosphorylation
MAPK3	unknown	GRB10	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	130.6×	2e-11
Activation of BAD and translocation to mitochondria	5	105.7×	1e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	93.3×	1e-07
Activation of BH3-only proteins	5	69.0×	5e-07
FOXO-mediated transcription	5	46.6×	3e-06
RHO GTPases activate PKNs	5	44.1×	3e-06
Intrinsic Pathway for Apoptosis	5	40.7×	4e-06
SARS-CoV-1-host interactions	7	34.2×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
insulin receptor signaling pathway	5	25.2×	3e-04
protein autophosphorylation	6	19.8×	2e-04
intracellular protein localization	6	14.3×	5e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	12.5×	3e-04
positive regulation of cell migration	7	9.8×	8e-04
negative regulation of apoptotic process	10	7.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	15
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

3768 predictions. Top by Δscore:

Variant	Effect	Δscore
7:50593095:CGCA:C	acceptor_gain	1.0000
7:50593097:CA:C	acceptor_gain	1.0000
7:50593098:ACT:A	acceptor_loss	1.0000
7:50593099:C:CC	acceptor_gain	1.0000
7:50593099:CTGGA:C	acceptor_loss	1.0000
7:50593100:T:C	acceptor_loss	1.0000
7:50605288:AC:A	donor_gain	1.0000
7:50605288:ACCCT:A	donor_gain	1.0000
7:50605289:CC:C	donor_gain	1.0000
7:50605289:CCCTC:C	donor_gain	1.0000
7:50605402:CTGCG:C	acceptor_gain	1.0000
7:50605403:TGCG:T	acceptor_gain	1.0000
7:50605405:CG:C	acceptor_gain	1.0000
7:50606331:ACTT:A	donor_loss	1.0000
7:50606332:CTT:C	donor_loss	1.0000
7:50606333:TTA:T	donor_loss	1.0000
7:50606334:TACCA:T	donor_loss	1.0000
7:50606335:A:AC	donor_gain	1.0000
7:50606335:A:AG	donor_loss	1.0000
7:50606335:AC:A	donor_gain	1.0000
7:50606336:C:CA	donor_loss	1.0000
7:50606336:C:CC	donor_gain	1.0000
7:50606336:CC:C	donor_gain	1.0000
7:50606336:CCA:C	donor_gain	1.0000
7:50606410:CCATA:C	acceptor_gain	1.0000
7:50606411:CATA:C	acceptor_gain	1.0000
7:50606411:CATAC:C	acceptor_gain	1.0000
7:50606413:TA:T	acceptor_gain	1.0000
7:50606414:AC:A	acceptor_loss	1.0000
7:50606415:C:CA	acceptor_loss	1.0000

AlphaMissense

3939 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:50592983:A:T	L585H	1.000
7:50593018:A:C	F573L	1.000
7:50593018:A:T	F573L	1.000
7:50593020:A:G	F573L	1.000
7:50593028:A:G	L570P	1.000
7:50593045:G:C	F564L	1.000
7:50593045:G:T	F564L	1.000
7:50593046:A:G	F564S	1.000
7:50593047:A:G	F564L	1.000
7:50595483:A:G	L531P	1.000
7:50595483:A:T	L531H	1.000
7:50595516:C:G	R520P	1.000
7:50595517:G:T	R520S	1.000
7:50604065:A:G	W493R	1.000
7:50604065:A:T	W493R	1.000
7:50605368:A:C	F437L	1.000
7:50605368:A:T	F437L	1.000
7:50605370:A:G	F437L	1.000
7:50592983:A:G	L585P	0.999
7:50592995:A:T	L581Q	0.999
7:50593019:A:G	F573S	0.999
7:50593025:A:T	V571D	0.999
7:50595444:A:G	I544T	0.999
7:50595477:A:G	L533P	0.999
7:50595483:A:C	L531R	0.999
7:50595486:A:T	V530E	0.999
7:50595509:G:C	S522R	0.999
7:50595509:G:T	S522R	0.999
7:50595511:T:G	S522R	0.999
7:50595522:A:G	L518P	0.999

dbSNP variants (sampled 300 via entrez): RS1000001901 (7:50665156 T>C), RS1000006449 (7:50679968 T>G), RS1000008978 (7:50628035 G>A), RS1000011560 (7:50775206 A>ACATT), RS1000019624 (7:50704242 T>C), RS1000061649 (7:50777102 T>C), RS1000063396 (7:50692330 T>A), RS1000115024 (7:50776822 T>G), RS1000145309 (7:50770821 T>C), RS1000154812 (7:50622293 A>G), RS1000155796 (7:50660675 A>G), RS1000159072 (7:50754636 A>T), RS1000160028 (7:50610938 A>C), RS1000163317 (7:50649000 T>C), RS1000216001 (7:50748141 A>G)

Disease associations

OMIM: gene MIM:601523 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000085	Horseshoe kidney
HP:0000110	Renal dysplasia
HP:0000119	Abnormality of the genitourinary system
HP:0000160	Narrow mouth
HP:0000201	Pierre-Robin sequence
HP:0000233	Thin vermilion border
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000678	Dental crowding
HP:0000691	Microdontia
HP:0000750	Delayed speech and language development
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000826	Precocious puberty
HP:0000855	Insulin resistance
HP:0000975	Hyperhidrosis
HP:0001156	Brachydactyly
HP:0001159	Syndactyly
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001328	Specific learning disability
HP:0001476	Delayed closure of the anterior fontanelle
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001620	Abnormally high-pitched voice
HP:0001627	Abnormal heart morphology

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST001160_6	Systemic sclerosis	1.000000e-06
GCST001527_9	Fasting blood glucose (BMI interaction)	8.000000e-08
GCST001912_1	Acute lymphoblastic leukemia (childhood)	2.000000e-29
GCST002587_37	Blood pressure (smoking interaction)	8.000000e-07
GCST002604_1	Schizophrenia (treatment resistant)	6.000000e-07
GCST002951_10	Response to zileuton treatment in asthma (FEV1 change interaction)	6.000000e-06
GCST004606_155	Eosinophil count	2.000000e-09
GCST004624_114	Sum eosinophil basophil counts	2.000000e-09
GCST005186_8	Fasting blood glucose	3.000000e-09
GCST005215_1	Corrected insulin response	3.000000e-09
GCST005216_1	Corrected insulin response adjusted for insulin sensitivity index	1.000000e-07
GCST005217_1	Insulin levels adjusted for BMI	1.000000e-09
GCST005218_1	Area under the curve of insulin levels	7.000000e-06
GCST005219_1	Incremental insulin	5.000000e-09
GCST005223_1	Ratio of the area under the curve for insulin and the area under the curve for glucose	8.000000e-07
GCST005348_107	Total body bone mineral density	4.000000e-08
GCST005348_76	Total body bone mineral density	1.000000e-08
GCST005950_9	Body mass index x sex x age interaction (4df test)	2.000000e-09
GCST005951_200	Body mass index	2.000000e-08
GCST005951_57	Body mass index	3.000000e-10
GCST005953_3	Body mass index (age <50)	8.000000e-10
GCST006423_8	Fracture	5.000000e-10
GCST006627_29	Diastolic blood pressure	3.000000e-12
GCST006979_126	Heel bone mineral density	2.000000e-20
GCST007565_188	Morning person	8.000000e-21
GCST007576_343	Chronotype	8.000000e-21
GCST007691_13	Femoral neck bone mineral density	3.000000e-06
GCST007876_102	Estimated glomerular filtration rate	3.000000e-09
GCST008058_28	Estimated glomerular filtration rate	4.000000e-11
GCST008059_166	Estimated glomerular filtration rate	1.000000e-10

EFO canonical traits (21, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0006336	diastolic blood pressure
EFO:0006525	cigarettes per day measurement
EFO:0005921	FEV change measurement
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0008473	insulin response measurement
EFO:0004471	insulin sensitivity measurement
EFO:0004467	insulin measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0008328	chronotype measurement
EFO:0007785	femoral neck bone mineral density
EFO:0004344	birth weight
EFO:0010352	diacylglycerol 34:1 measurement
EFO:0004346	neuroimaging measurement
EFO:0004980	appendicular lean mass
EFO:0010701	mean reticulocyte volume
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3621028 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	6
Arsenic Trioxide	increases cleavage, affects cotreatment, increases expression, affects response to substance, decreases expression (+2 more)	4
sodium arsenite	increases expression, affects cotreatment, decreases expression	3
Valproic Acid	affects expression, decreases expression, decreases methylation	3
Cyclosporine	increases expression	3
bisphenol A	increases expression, affects methylation, affects cotreatment	2
cobaltous chloride	increases expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression, affects cotreatment	2
Cadmium	decreases expression, decreases reaction, affects expression	2
Carbamazepine	affects expression	2
Estradiol	affects expression, affects cotreatment, increases expression	2
Rotenone	increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	increases reaction, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	increases methylation	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
moringin	decreases expression, affects cotreatment	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
lead acetate	decreases expression, affects cotreatment	1
pyrazolo(3,4-d)pyrimidine	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium bichromate	decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3624734	Binding	Binding affinity to GST-tagged Grb10-SH2 domain (471 to 594 amino acid residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) using 20 mM Tris/1 mM NaPO4 buffer by SPR analysis	Cyclic Peptides Incorporating Phosphotyrosine Mimetics as Potent and Specific Inhibitors of the Grb7 Breast Cancer Target. — J Med Chem

Clinical trials (associated diseases)

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