GRB7

Summary

GRB7 (growth factor receptor bound protein 7, HGNC:4567) is a protein-coding gene on chromosome 17q12, encoding Growth factor receptor-bound protein 7 (Q14451). Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling.

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 epidermal growth factor receptor (EGFR) and ephrin receptors. The protein plays a role in the integrin signaling pathway and cell migration by binding with focal adhesion kinase (FAK). Several transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 2886 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 100 total
• Druggable target: yes
• MANE Select transcript: NM_005310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4567
Approved symbol	GRB7
Name	growth factor receptor bound protein 7
Location	17q12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141738
Ensembl biotype	protein_coding
OMIM	601522
Entrez	2886

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 36 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000309156, ENST00000394204, ENST00000394209, ENST00000394211, ENST00000445327, ENST00000461756, ENST00000473071, ENST00000485182, ENST00000577695, ENST00000578702, ENST00000583813, ENST00000584053, ENST00000584819, ENST00000584853, ENST00000894755, ENST00000894756, ENST00000894757, ENST00000894758, ENST00000894759, ENST00000894760, ENST00000894761, ENST00000894762, ENST00000894763, ENST00000894764, ENST00000894765, ENST00000894766, ENST00000894767, ENST00000894768, ENST00000894769, ENST00000894770, ENST00000923423, ENST00000923424, ENST00000923425, ENST00000923426, ENST00000923427, ENST00000923428, ENST00000923429, ENST00000923430, ENST00000923431, ENST00000923432, ENST00000923433, ENST00000923434, ENST00000968448, ENST00000968449

RefSeq mRNA: 5 — MANE Select: NM_005310 NM_001030002, NM_001242442, NM_001242443, NM_001330207, NM_005310

CCDS: CCDS11345, CCDS56028, CCDS82116

Canonical transcript exons

ENST00000309156 — 15 exons

Exon	Start	End
ENSE00000950638	39742898	39743054
ENSE00000950642	39744553	39744663
ENSE00000950643	39744886	39744984
ENSE00000950644	39745243	39745323
ENSE00000950645	39745422	39745538
ENSE00000950646	39745728	39745788
ENSE00000950647	39745913	39746000
ENSE00001850980	39746751	39747285
ENSE00003500024	39744070	39744207
ENSE00003545200	39743180	39743301
ENSE00003590542	39746109	39746202
ENSE00003652777	39742566	39742716
ENSE00003660479	39743393	39743470
ENSE00003687545	39742252	39742456
ENSE00003842366	39737938	39738133

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 97.97.

FANTOM5 (CAGE): breadth broad, TPM avg 6.3908 / max 390.2156, expressed in 670 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160631	3.4343	500
160630	1.5153	474
160629	1.2351	500
160628	0.2061	109

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.97	gold quality
lower esophagus mucosa	UBERON:0035834	97.62	gold quality
metanephros cortex	UBERON:0010533	96.94	gold quality
secondary oocyte	CL:0000655	95.51	gold quality
right uterine tube	UBERON:0001302	95.31	gold quality
esophagus mucosa	UBERON:0002469	94.75	gold quality
body of pancreas	UBERON:0001150	94.55	gold quality
skin of abdomen	UBERON:0001416	94.19	gold quality
skin of leg	UBERON:0001511	93.60	gold quality
minor salivary gland	UBERON:0001830	91.34	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.12	gold quality
zone of skin	UBERON:0000014	90.09	gold quality
mouth mucosa	UBERON:0003729	88.55	gold quality
pancreas	UBERON:0001264	88.48	gold quality
saliva-secreting gland	UBERON:0001044	87.02	gold quality
right lobe of liver	UBERON:0001114	86.20	gold quality
mucosa of transverse colon	UBERON:0004991	86.17	gold quality
gall bladder	UBERON:0002110	85.91	gold quality
adult mammalian kidney	UBERON:0000082	85.87	gold quality
rectum	UBERON:0001052	85.08	gold quality
right lung	UBERON:0002167	84.55	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.32	gold quality
body of stomach	UBERON:0001161	84.20	gold quality
cerebellar hemisphere	UBERON:0002245	83.95	gold quality
cerebellar cortex	UBERON:0002129	83.77	gold quality
vagina	UBERON:0000996	83.62	gold quality
upper lobe of left lung	UBERON:0008952	83.49	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.36	gold quality
upper lobe of lung	UBERON:0008948	82.37	gold quality
left lobe of thyroid gland	UBERON:0001120	82.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	8.09
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting GRB7, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4468	98.01	66.85	1187
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-2278	97.30	66.19	1130

Literature-anchored findings (GeneRIF, showing 40)

• Identification of novel non-phosphorylated ligands, which bind selectively to the SH2 domain of Grb7 (PMID:11809769)
• Investigation of the GRB2, GRB7, and CSH1 genes as candidates for the Silver-Russell syndrome (SRS) on chromosome 17q. (PMID:11897833)
• the PH domain mediated Grb7 binding to phospholipids (PMID:12021278)
• NMR assignments of backbone 1H, 13C, and 15N resonances of Grb7-SH2 domain in complex with a phosphorylated peptide ligand (PMID:12061724)
• review of GRB7 binding sites and molecular interactions, and role in progression and invasive potential in cancer, making it a target for therapeutics (PMID:14585167)
• Oncogenomic recombination hotspot around the PPP1R1B-STARD3-TCAP-PNMT-PERLD1-ERBB2-C17orf37-GRB7 amplicon at human chromosome 17q12 is closely linked to evolutionary recombination hotspot around the GSDML-GSDM locus. (PMID:15010812)
• Incresaed Grb7 expression is associated with disease progression in chronic lymphocytic leukemia (PMID:15470489)
• Human Grb7 specifically binds CaM in a calcium2+-dependent manner; possible alterations of the Grb7/CaM system in tumor cells could be relevant to high motility seen in many cancer cells (PMID:15806159)
• Grb7-SH2 domain dimerisation depends on a single point mutation (PMID:15841400)
• Mutation and elevated expression of GRB7 is associated with the development of testicular germ cell tumors (PMID:16354586)
• Grb7 expression was statistically significantly different between specimens from patients with or without lymph node metastasis. (PMID:16595785)
• The Grb7 peptide has potential to be developed as a therapeutic agent alone, or in combination with traditional chemotherapy. (PMID:17426702)
• Grb7 plays an important role in hepatocellular carcinoma progression and is strongly associated with expression of focal adhesion kinase. (PMID:17634422)
• The solution structure and the backbone relaxation behavior of the Grb7-SH2/erbB2 peptide complex. (PMID:17705331)
• GRB-7 over-expression plays pivotal roles in activating signal transduction and promoting tumor growth in breast cancer cells with chromosome 17q11-21 amplification (PMID:17916906)
• Formation of focal adhesion kinase *Grb7 complexes and Grb7 phosphorylation by FAK in an integrin-dependent manner were essential for cell migration, proliferation and anchorage-independent growth in A431 epidermal carcinoma cells. (PMID:19473962)
• Results illuminate the membrane-recruitment mechanisms of Grb7, Grb10 and Grb14. (PMID:19648926)
• High Grb7 is associated with breast cancer. (PMID:19717535)
• Data show that Grb7 removal by RNA-interference reduces breast cancer cell viability. (PMID:20126311)
• proposed helix-swapping of the SH2 domain of Grb7, a regulatory protein implicated in cancer progression and inflammation (PMID:20370637)
• Studies implicate that the overexpressed GRB7 and GRB7v are associated with high-grade tumors and exert distinct tumorigenic functions through regulating different signaling pathways in ovarian cancer cells. (PMID:20388850)
• Findings illustrate an underlying mechanism by which Grb7 promotes tumorigenesis through the formation of a novel EGFR-Grb7-Ras signaling complex, thereby highlighting the potential strategy of targeting Grb7 as an anti-breast cancer therapy. (PMID:20622016)
• GRB7 protein over-expression is an independent adverse prognostic factor in human breast cancer (PMID:20635137)
• Full-length Grb7 and Hax-1 interact in mammalian cells and Grb7 is tyrosine phosphorylated. (PMID:20665473)
• X-ray diffraction data were collected from crystals to 2.4A resolution for G7-18NATE in complex with its Grb7 SH2 domain. (PMID:21139214)
• A series of Grb7 SH2 domain-binding nonphosphorylated peptides in the yeast two-hybrid system, were identified. (PMID:22253820)
• GRB7 is a context-dependent oncogene, which modulates the ERBB2 signaling pathway through enhanced phosphorylation of ERBB2 and Akt. (PMID:22584052)
• propose that CaM inhibits the translocation of Grb7 to the nucleus after binding to its CaM-BD and therefore occluding its overlapping NLS (PMID:22673522)
• Data propose the phosphorylation state of Grb7-SH2 domain tyrosine residues could control Grb7 dimerization, and dimerization may be an important regulatory step in Grb7 binding to RTKs such as erbB2. (PMID:22811067)
• Data suggest that calmodulin controls Grb7-mediated cell migration. (PMID:23743201)
• Grb7 protein interacts with Filamin-a, an actin-crosslinking component of the cell cytoskeleton. (PMID:24089360)
• The data reveal that Grb7 plays an important role in breast cancer progression, beyond the context of HER2+ve cell types (PMID:24464577)
• apo Grb7 SH2 domain crystallized in the trigonal space group P63, whereas the G7-B1-Grb7 SH2 domain complex crystallized in the monoclinic space group P21 (PMID:24637751)
• Grb7 was found to be significantly related to the biological classification of breast cancer (PMID:25182704)
• Suggest close relationship between Grb7 gene amplification and GRB7 protein overexpression in human ovarian cancer. Immunohistochemistry might have limited diagnostic value in these tumors compared to fluorescence in situ hybridization. (PMID:26617853)
• Study provided a direct link between the signal adapter protein Grb7, anti-apoptotic protein Hax1 isoform 1, and Caspase3-mediated apoptosis pathways, and suggests that besides modulating cell migration and signal transduction, Grb7 may also participate in Hax1-related apoptosis pathways mediated by Caspase3. (PMID:26869103)
• data shows that GRB7 expression in invasive breast cancer correlates with markers of a more aggressive phenotype, including HER2 overexpression, a greater degree of HER2 amplification, ER negativity, and p53 positivity (PMID:26945445)
• The crystal structure of a stapled bicyclic peptide inhibitor G7-B1 in complex with the Grb7-SH2 domain. (PMID:27257138)
• Grb7 protein Ras-associating domain oligomerization has been reported. (PMID:28295715)
• Our results indicated that Grb7 over-expression may facilitate invasion and inhibit apoptosis in cervical cancer (PMID:28780081)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	grb7	ENSDARG00000042726
mus_musculus	Grb7	ENSMUSG00000019312
rattus_norvegicus	Grb7	ENSRNOG00000006990
drosophila_melanogaster	pico	FBGN0261811
caenorhabditis_elegans		WBGENE00003243

Paralogs (4): APBB1IP (ENSG00000077420), GRB10 (ENSG00000106070), GRB14 (ENSG00000115290), RAPH1 (ENSG00000173166)

Protein

Protein identifiers

Growth factor receptor-bound protein 7 — Q14451 (reviewed: Q14451)

Alternative names: B47, Epidermal growth factor receptor GRB-7, GRB7 adapter protein

All UniProt accessions (4): A0A0S2Z4F6, Q14451, J3QKK7, J3QL76

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling. Promotes activation of down-stream protein kinases, including STAT3, AKT1, MAPK1 and/or MAPK3. Promotes activation of HRAS. Plays a role in signal transduction in response to EGF. Plays a role in the regulation of cell proliferation and cell migration. Plays a role in the assembly and stability of RNA stress granules. Binds to the 5’UTR of target mRNA molecules and represses translation of target mRNA species, when not phosphorylated. Phosphorylation impairs RNA binding and promotes stress granule disassembly during recovery after cellular stress.

Subunit / interactions. Homodimer. Interacts (via SH2 domain) with EGFR, ERBB2, ERBB3 (when phosphorylated), ERBB4 (when phosphorylated), EPHB1, INSR, FGFR1, PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with SHC1. Interacts with RND1. Interacts (when tyrosine phosphorylated) with FHL2 and HAX1. Interacts (via SH2 domain) with RET and PTK2/FAK1. Interacts (when not phosphorylated) with ELAVL1. In stressed cells, but not in normal cells, part of a complex that contains at least GRB7, PTK2/FAK1, STAU1, ELAVL1 and TIA1. Interacts (via SH2 domain) with KIT (phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated).

Subcellular location. Cytoplasm. Cell junction. Focal adhesion. Cell membrane. Cytoplasmic granule. Cell projection.

Post-translational modifications. Phosphorylated on serine and threonine residues in response to heregulin. Phosphorylated on tyrosine residues by TEK/TIE2. Phosphorylated on tyrosine residues in response to NTN1 signaling. Phosphorylation promotes stress granule disassembly during recovery after cellular stress. Phosphorylated on tyrosine residues by PTK2/FAK1, and possibly also other kinases. Phosphorylation is enhanced by activation of receptor kinases. Tyrosine phosphorylation is essential for activation of down-stream protein kinases.

Domain organisation. The PH domain mediates interaction with membranes containing phosphoinositides.

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

Isoforms (4)

UniProt ID	Names	Canonical?
Q14451-1	1	yes
Q14451-2	2, Grb7V
Q14451-3	3
Q14451-4	4

RefSeq proteins (5): NP_001025173, NP_001229371, NP_001229372, NP_001317136, NP_005301* (*=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
IPR035032	Grb7_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR039664	GRB/APBB1IP	Family
IPR039665	PH_APBB1IP	Domain
IPR046986	GRB7_RA	Domain

Pfam: PF00017, PF00169, PF08947, PF21989

UniProt features (58 total): strand 17, mutagenesis site 10, sequence conflict 7, helix 7, splice variant 4, domain 3, modified residue 3, compositionally biased region 2, site 2, chain 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
5EEQ	X-RAY DIFFRACTION	1.6
4WWQ	X-RAY DIFFRACTION	1.8
2QMS	X-RAY DIFFRACTION	2.1
5U06	X-RAY DIFFRACTION	2.1
5U1Q	X-RAY DIFFRACTION	2.1
5TYI	X-RAY DIFFRACTION	2.15
3PQZ	X-RAY DIFFRACTION	2.41
5EEL	X-RAY DIFFRACTION	2.47
4X6S	X-RAY DIFFRACTION	2.55
7MP3	X-RAY DIFFRACTION	2.55
5D0J	X-RAY DIFFRACTION	2.6
1MW4	SOLUTION NMR
1WGR	SOLUTION NMR
2L4K	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14451-F1	79.04	0.54

Functional residue map

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

Catalytic / active sites (2): 239 (important for lipid binding and for stimulation of cell migration); 511 (important for dimerization and for hras activation)

Post-translational modifications (3): 338, 361, 188

Mutagenesis-validated functional residues (10):

Position	Phenotype
188	abolishes ras activity increase and erk1/2 phosphorylation.
239	abolishes phosphoinositide binding.
259	global loss of tyrosine phosphorylation. abolishes interaction with fhl2 and hax1.
260	global loss of tyrosine phosphorylation. abolishes interaction with fhl2 and hax1.
284	global loss of tyrosine phosphorylation. abolishes interaction with fhl2 and hax1.
338	abolishes ras activity increase and erk1/2 phosphorylation.
458	impairs phosphotyrosine binding by sh2 domain.
480	global loss of tyrosine phosphorylation. abolishes interaction with fhl2 and hax1.
492	global loss of tyrosine phosphorylation. abolishes interaction with fhl2 and hax1.
511	abolishes dimerization. abolishes activation of hras.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1306955	GRB7 events in ERBB2 signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-186763	Downstream signal transduction
R-HSA-210993	Tie2 Signaling
R-HSA-8853659	RET signaling
R-HSA-9696273	RND1 GTPase cycle

MSigDB gene sets: 231 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GRUETZMANN_PANCREATIC_CANCER_DN, GCANCTGNY_MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, FOXO1_01, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, FOXD3_01, REACTOME_TIE2_SIGNALING, GOBP_TRANSLATION, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, MUELLER_PLURINET

GO Biological Process (5): epidermal growth factor receptor signaling pathway (GO:0007173), negative regulation of translation (GO:0017148), positive regulation of cell migration (GO:0030335), stress granule assembly (GO:0034063), signal transduction (GO:0007165)

GO Molecular Function (6): RNA binding (GO:0003723), protein kinase binding (GO:0019901), phosphatidylinositol binding (GO:0035091), identical protein binding (GO:0042802), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (8): cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cytoplasmic stress granule (GO:0010494), cell projection (GO:0042995), cytoplasm (GO:0005737), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by ERBB2	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by PDGF	1
Cell surface interactions at the vascular wall	1
Axon guidance	1
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	2
ERBB signaling pathway	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
membraneless organelle assembly	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
nucleic acid binding	1
kinase binding	1
anion binding	1
protein binding	1
cytoplasm	1
membrane	1
cell periphery	1
cell-substrate junction	1
cytoplasmic ribonucleoprotein granule	1
intracellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1859 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRB7	ERBB2	P04626	990
GRB7	EGFR	P00533	967
GRB7	SHC1	P29353	879
GRB7	LY6G6F	Q5SQ64	839
GRB7	STARD3	Q14849	817
GRB7	SRC	P12931	803
GRB7	ERBB3	P21860	799
GRB7	GRB2	P29354	753
GRB7	ERBB4	Q15303	745
GRB7	ZPBP2	Q6X784	726
GRB7	MIEN1	Q9BRT3	720
GRB7	PGAP3	Q96FM1	715
GRB7	RND1	Q92730	708
GRB7	ZPBP	Q9BS86	670
GRB7	KIT	P10721	665

IntAct

113 interactions, top by confidence:

A	B	Type	Score
GRB7	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.780
ERBB2	GRB7	psi-mi:“MI:0407”(direct interaction)	0.780
GRB7	ERBB2	psi-mi:“MI:0914”(association)	0.780
ERBB3	PIK3R2	psi-mi:“MI:0914”(association)	0.700
GRB7	ERBB3	psi-mi:“MI:0407”(direct interaction)	0.690
GRB7	ERBB3	psi-mi:“MI:0914”(association)	0.690
GRB7	LAX1	psi-mi:“MI:0915”(physical association)	0.670
LAX1	GRB7	psi-mi:“MI:0915”(physical association)	0.670
GRB7	KIT	psi-mi:“MI:0914”(association)	0.590
GRB7	KIT	psi-mi:“MI:0407”(direct interaction)	0.590
GRB7	RND1	psi-mi:“MI:0915”(physical association)	0.580
RND1	GRB7	psi-mi:“MI:0915”(physical association)	0.580
GRB7	PTK2	psi-mi:“MI:0915”(physical association)	0.570
OLIG1	GRB7	psi-mi:“MI:0915”(physical association)	0.570
GRB7	OLIG1	psi-mi:“MI:0915”(physical association)	0.570
PTK2	GRB7	psi-mi:“MI:0915”(physical association)	0.570

BioGRID (217): LAX1 (Two-hybrid), TRIM36 (Two-hybrid), KCTD6 (Two-hybrid), OLIG1 (Two-hybrid), PTK2 (Two-hybrid), ZNHIT1 (Two-hybrid), GRB7 (Affinity Capture-Luminescence), GRB7 (Affinity Capture-Luminescence), GRB7 (Affinity Capture-MS), PTK2 (Reconstituted Complex), GRB7 (Affinity Capture-MS), GRB7 (Two-hybrid), GRB7 (Two-hybrid), PDGFRB (Affinity Capture-Western), PDGFRB (Reconstituted Complex)

ESM2 similar proteins: A5PJU7, A8MQ27, F1MLB4, F1MX48, F1SAM7, I3L5V6, O75425, O95382, P36916, Q08DG4, Q0MW30, Q14451, Q2YD98, Q32P44, Q3MIP1, Q3T033, Q3UPE3, Q3UV16, Q505F5, Q5EBM0, Q5U651, Q5ZM20, Q641Q3, Q6MG06, Q6SZW1, Q6ZTW0, Q7T0L4, Q8BGG6, Q8BH83, Q8C0R7, Q8K0Y7, Q8N9W5, Q8R2K4, Q8TE68, Q8VC03, Q96BM1, Q96E14, Q96EF6, Q96EY9, Q99JB7

Diamond homologs: A6NKC9, A6X942, O88834, P00519, P00520, P00521, P10447, P20936, P29353, P32577, P41239, P41240, P41241, P42684, P50904, P98083, Q03160, Q08012, Q08CX2, Q0IIE2, Q0VBZ0, Q14451, Q15464, Q1RMW5, Q4JIM5, Q56A36, Q5SQS7, Q6AYC8, Q6PD21, Q6VYH9, Q6YKA8, Q8BI17, Q96IW2, Q96JZ2, Q9D7V1, Q9H788, Q9NP31, Q9QXK9, Q9QZC5, A0A8I3NFE2

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
KIT	“up-regulates activity”	GRB7	binding
PTPN11	“up-regulates activity”	GRB7	dephosphorylation
MAPK8	“down-regulates quantity by destabilization”	GRB7	phosphorylation
RET	up-regulates	GRB7	binding
GRB7	up-regulates	RND1	binding
INSR	up-regulates	GRB7	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 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
Constitutive Signaling by Aberrant PI3K in Cancer	8	24.8×	2e-07
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	18.9×	1e-06
RAF/MAP kinase cascade	11	16.4×	2e-08
PIP3 activates AKT signaling	8	13.0×	2e-05
MAPK family signaling cascades	5	12.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	6	32.3×	2e-05
cell surface receptor protein tyrosine kinase signaling pathway	5	18.9×	2e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	10.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2169 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39742717:G:GG	donor_gain	1.0000
17:39742872:A:G	acceptor_gain	1.0000
17:39743165:T:TA	acceptor_gain	1.0000
17:39743171:T:TA	acceptor_gain	1.0000
17:39743175:CCCA:C	acceptor_loss	1.0000
17:39743177:CAGA:C	acceptor_loss	1.0000
17:39743178:A:AG	acceptor_gain	1.0000
17:39743178:A:C	acceptor_loss	1.0000
17:39743178:AGAGC:A	acceptor_gain	1.0000
17:39743179:G:GA	acceptor_gain	1.0000
17:39743179:GA:G	acceptor_gain	1.0000
17:39743179:GAGC:G	acceptor_gain	1.0000
17:39743179:GAGCG:G	acceptor_gain	1.0000
17:39743272:GCCAA:G	donor_gain	1.0000
17:39743277:G:GG	donor_gain	1.0000
17:39743302:G:GG	donor_gain	1.0000
17:39744062:T:A	acceptor_gain	1.0000
17:39744063:G:A	acceptor_gain	1.0000
17:39744068:A:AG	acceptor_gain	1.0000
17:39744069:G:GG	acceptor_gain	1.0000
17:39744548:CTTA:C	acceptor_loss	1.0000
17:39744549:TTAG:T	acceptor_loss	1.0000
17:39744551:A:AG	acceptor_gain	1.0000
17:39744552:G:GG	acceptor_gain	1.0000
17:39744881:T:TA	acceptor_gain	1.0000
17:39744882:GCA:G	acceptor_loss	1.0000
17:39744883:CAGC:C	acceptor_loss	1.0000
17:39744884:A:AG	acceptor_gain	1.0000
17:39744884:A:C	acceptor_loss	1.0000
17:39744885:G:GG	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000106146 (17:39742842 A>G), RS1000180125 (17:39737641 C>T), RS1000232299 (17:39737940 T>C), RS1000569285 (17:39746321 C>A,T), RS1001010065 (17:39740993 C>A,G,T), RS1001101339 (17:39743926 G>A), RS1001206981 (17:39739632 C>T), RS1001675156 (17:39745195 C>A,T), RS1001813813 (17:39738985 G>A,C), RS1002203214 (17:39740901 A>G), RS1002782705 (17:39737869 CCCTCCTCCCAGGTTT>C), RS1002818508 (17:39740593 G>A), RS1002992867 (17:39743908 A>ACTTGAG), RS1003084509 (17:39746478 A>G), RS1003230562 (17:39739165 A>C,G,T)

Disease associations

OMIM: gene MIM:601522 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000624_15	Ulcerative colitis	3.000000e-08
GCST003155_23	Systemic lupus erythematosus	8.000000e-09
GCST004131_33	Inflammatory bowel disease	2.000000e-26
GCST004132_116	Crohn’s disease	1.000000e-16
GCST004133_16	Ulcerative colitis	2.000000e-16
GCST004390_3	Asthma	1.000000e-12
GCST007564_21	Asthma or allergic disease (pleiotropy)	4.000000e-17
GCST008839_284	Height	1.000000e-08
GCST008916_10	Asthma	5.000000e-09
GCST008916_21	Asthma	2.000000e-62
GCST008916_45	Asthma	3.000000e-10
GCST008916_86	Asthma	2.000000e-14
GCST010002_123	Refractive error	1.000000e-24
GCST011457_20	Asthma with severe exacerbations	1.000000e-10
GCST011773_38	Type 1 diabetes (age at diagnosis)	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004918	age at diagnosis

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1649051 (SINGLE PROTEIN)

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

ChEMBL bioactivities

23 potent at pChembl≥5 of 29 total, top 23 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.89	Kd	130	nM	CHEMBL4069253
6.66	Kd	220	nM	CHEMBL4093671
6.57	Kd	270	nM	CHEMBL4072970
6.08	Kd	830	nM	CHEMBL4069253
6.08	Kd	830	nM	CHEMBL4078046
5.96	Kd	1100	nM	CHEMBL4072970
5.68	Kd	2100	nM	CHEMBL3623450
5.59	Kd	2560	nM	CHEMBL4101397
5.58	Kd	2600	nM	CHEMBL3623448
5.54	Kd	2900	nM	CHEMBL3623448
5.53	Kd	2940	nM	CHEMBL4093671
5.52	Kd	3030	nM	CHEMBL4083407
5.51	Kd	3060	nM	CHEMBL1642691
5.41	Kd	3900	nM	CHEMBL3623449
5.39	Kd	4100	nM	CHEMBL3623448
5.39	Kd	4100	nM	CHEMBL4095044
5.30	Kd	5060	nM	CHEMBL1642687
5.24	Kd	5700	nM	CHEMBL3623449
5.24	Kd	5760	nM	CHEMBL1642690
5.18	Kd	6570	nM	CHEMBL3623450
5.18	Kd	6570	nM	CHEMBL1642688
5.15	Kd	7120	nM	CHEMBL1642689
5.11	Kd	7810	nM	CHEMBL4083407

PubChem BioAssay actives

23 with measured affinity, of 89 total; 15 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[[(1S,4S,7S,10S,16S,19S,22S,28R)-4-(2-amino-2-oxoethyl)-19-benzyl-28-carbamoyl-16-(2-carboxyethyl)-7-(carboxymethyl)-3,6,9,12,15,18,21,24,30,33-decaoxo-26-thia-2,5,8,11,14,17,20,23,29,34-decazabicyclo[20.8.8]octatriacontan-10-yl]methyl]benzoic acid	1476918: Binding affinity to human GST-tagged GRB7-SH2 domain (415 to 594 residues) expressed in Escherichia coli BL21(DE3) pLys after 60 to 80 secs in presence of 1 mM phosphate buffer by SPR assay	kd	0.1300	uM
3-[(1S,4S,7S,10S,16S,19S,22S,28R)-4-(2-amino-2-oxoethyl)-19-benzyl-28-carbamoyl-7-(carboxymethyl)-10-[[4-(carboxymethyl)phenyl]methyl]-3,6,9,12,15,18,21,24,30,33-decaoxo-26-thia-2,5,8,11,14,17,20,23,29,34-decazabicyclo[20.8.8]octatriacontan-16-yl]propanoic acid	1476918: Binding affinity to human GST-tagged GRB7-SH2 domain (415 to 594 residues) expressed in Escherichia coli BL21(DE3) pLys after 60 to 80 secs in presence of 1 mM phosphate buffer by SPR assay	kd	0.2200	uM
3-[(1S,4S,7S,10S,16S,19S,22S,28R)-4-(2-amino-2-oxoethyl)-19-benzyl-28-carbamoyl-7-(carboxymethyl)-10-[(4-hydroxyphenyl)methyl]-3,6,9,12,15,18,21,24,30,33-decaoxo-26-thia-2,5,8,11,14,17,20,23,29,34-decazabicyclo[20.8.8]octatriacontan-16-yl]propanoic acid	1476917: Binding affinity to human GST-tagged GRB7-SH2 domain (415 to 594 residues) expressed in Escherichia coli BL21(DE3) pLys after 60 to 80 secs in presence of 50 mM phosphate buffer by SPR assay	kd	0.2700	uM
3-[(1S,4R,7S,10S,16R,19S,22S,28R,34Z)-4-(2-amino-2-oxoethyl)-19-benzyl-28-carbamoyl-7-(carboxymethyl)-10-[(4-hydroxyphenyl)methyl]-3,6,9,12,15,18,21,24,30-nonaoxo-32,37-dioxa-26-thia-2,5,8,11,14,17,20,23,29-nonazabicyclo[20.8.8]octatriacont-34-en-16-yl]propanoic acid	1476928: Binding affinity to GST-tagged GRB7-SH2 (415 to 532 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) in 50 mM sodium phosphate buffer by SPR analysis	kd	0.8300	uM
4-[[(3S,6S,9S,12S,15S,21S,24S,27S,33R,36S)-9-(2-amino-2-oxoethyl)-3,24-dibenzyl-33-carbamoyl-21-(2-carboxyethyl)-12-(carboxymethyl)-6-[(1R)-1-hydroxyethyl]-27-(1H-indol-2-ylmethyl)-2,5,8,11,14,17,20,23,26,29,35-undecaoxo-31-thia-1,4,7,10,13,16,19,22,25,28,34-undecazabicyclo[34.3.0]nonatriacontan-15-yl]methyl]benzoic acid	1251151: Binding affinity to GST-tagged Grb7-SH2 domain (415 to 532 amino acid residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) using 20 mM Tris/1 mM NaPO4 buffer by SPR analysis	kd	2.1000	uM
3-[(1S,4S,7S,10S,16S,19S,22S,28R)-4-(2-amino-2-oxoethyl)-19-benzyl-28-carbamoyl-7-(carboxymethyl)-10-[(4-hydroxyphenyl)methyl]-3,6,9,12,15,18,21,24,30,36-decaoxo-26-thia-2,5,8,11,14,17,20,23,29,35-decazabicyclo[20.8.8]octatriacontan-16-yl]propanoic acid	1476917: Binding affinity to human GST-tagged GRB7-SH2 domain (415 to 594 residues) expressed in Escherichia coli BL21(DE3) pLys after 60 to 80 secs in presence of 50 mM phosphate buffer by SPR assay	kd	2.5600	uM
3-[(3S,6S,9S,12S,15S,21S,24S,27S,33R,36S)-9-(2-amino-2-oxoethyl)-3,24-dibenzyl-33-carbamoyl-12-(carboxymethyl)-6-[(1R)-1-hydroxyethyl]-15-[(4-hydroxyphenyl)methyl]-27-(1H-indol-2-ylmethyl)-2,5,8,11,14,17,20,23,26,29,35-undecaoxo-31-thia-1,4,7,10,13,16,19,22,25,28,34-undecazabicyclo[34.3.0]nonatriacontan-21-yl]propanoic acid	1251150: Binding affinity to GST-tagged Grb7-SH2 domain (415 to 532 amino acid residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) using 350 mM NaPO4 buffer by SPR analysis	kd	2.6000	uM
3-[(1S,4S,7S,10S,16S,19S,22S,35R)-4-(2-amino-2-oxoethyl)-19-benzyl-35-carbamoyl-7-(carboxymethyl)-10-[(4-hydroxyphenyl)methyl]-3,6,9,12,15,18,21,33,39-nonaoxo-24-oxa-37-thia-2,5,8,11,14,17,20,27,28,29,34,40-dodecazatricyclo[20.10.8.126,29]hentetraconta-26(41),27-dien-16-yl]propanoic acid	1476917: Binding affinity to human GST-tagged GRB7-SH2 domain (415 to 594 residues) expressed in Escherichia coli BL21(DE3) pLys after 60 to 80 secs in presence of 50 mM phosphate buffer by SPR assay	kd	3.0300	uM
methyl 3-(6-benzoyl-3-oxo-4H-quinoxalin-2-yl)-5-(4-methylanilino)-2,4,5-trioxopentanoate	551133: Binding affinity to human GRB7 expressed in Escherichia coli BL21 (DE3) by isothermal titration calorimetry	kd	3.0600	uM
3-[(3S,6S,9S,12S,15S,21S,24S,27S,33R,36S)-9-(2-amino-2-oxoethyl)-3,24-dibenzyl-33-carbamoyl-12-(carboxymethyl)-15-[[4-(carboxymethyl)phenyl]methyl]-6-[(1R)-1-hydroxyethyl]-27-(1H-indol-2-ylmethyl)-2,5,8,11,14,17,20,23,26,29,35-undecaoxo-31-thia-1,4,7,10,13,16,19,22,25,28,34-undecazabicyclo[34.3.0]nonatriacontan-21-yl]propanoic acid	1251148: Binding affinity to GST-tagged Grb7-SH2 domain (415 to 532 amino acid residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) using 20 mM Tris buffer by SPR analysis	kd	3.9000	uM
3-[(3S,6S,9S,12S,15S,21S,24S,27S,33R,36S)-9-(2-amino-2-oxoethyl)-3,24-dibenzyl-33-carbamoyl-12-(carboxymethyl)-6-[(1R)-1-hydroxyethyl]-15-[(4-hydroxyphenyl)methyl]-27-(1H-indol-3-ylmethyl)-2,5,8,11,14,17,20,23,26,29,35-undecaoxo-31-thia-1,4,7,10,13,16,19,22,25,28,34-undecazabicyclo[34.3.0]nonatriacontan-21-yl]propanoic acid	1476928: Binding affinity to GST-tagged GRB7-SH2 (415 to 532 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) in 50 mM sodium phosphate buffer by SPR analysis	kd	4.1000	uM
methyl 3-(6-benzoyl-3-oxo-4H-quinoxalin-2-yl)-5-(2,5-dimethylanilino)-2,4,5-trioxopentanoate	551133: Binding affinity to human GRB7 expressed in Escherichia coli BL21 (DE3) by isothermal titration calorimetry	kd	5.0600	uM
methyl 5-(2-ethyl-6-propan-2-ylanilino)-2,4,5-trioxo-3-(3-oxo-4H-quinoxalin-2-yl)pentanoate	551133: Binding affinity to human GRB7 expressed in Escherichia coli BL21 (DE3) by isothermal titration calorimetry	kd	5.7600	uM
methyl 5-(2-cyano-4-nitroanilino)-3-(6-nitro-3-oxo-4H-quinoxalin-2-yl)-2,4,5-trioxopentanoate	551133: Binding affinity to human GRB7 expressed in Escherichia coli BL21 (DE3) by isothermal titration calorimetry	kd	6.5700	uM
methyl 5-(3-acetylanilino)-2,4,5-trioxo-3-(3-oxo-4H-quinoxalin-2-yl)pentanoate	551133: Binding affinity to human GRB7 expressed in Escherichia coli BL21 (DE3) by isothermal titration calorimetry	kd	7.1200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression	3
graphene oxide	increases expression	2
sodium arsenite	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
sotorasib	affects cotreatment, decreases expression	1
4-oxoretinoic acid	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	affects expression	1
lead acetate	decreases expression	1
beta-lapachone	increases expression	1
afimoxifene	decreases response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
tanshinone	increases expression	1
methacrylaldehyde	increases expression, increases abundance, affects cotreatment	1
perfluoro-n-nonanoic acid	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases response to substance	1
Leflunomide	decreases expression	1
Alitretinoin	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Vehicle Emissions	decreases expression, increases abundance	1

ChEMBL screening assays

24 unique, capped per target: 24 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1648139	Binding	Binding affinity to human GRB7 SH2-apo domain expressed in Escherichia coli BL21 (DE3) assessed as change in melting temperature at 100 uM by thermofluor based melting point shift assay	Benzopyrazine derivatives: A novel class of growth factor receptor bound protein 7 antagonists. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E4WX	ZR-75-1 GRB7 clone 3	Cancer cell line	Female
CVCL_E4WY	ZR-75-1 GRB7 clone 4	Cancer cell line	Female

Clinical trials (associated diseases)

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