SHC2

Summary

SHC2 (SHC adaptor protein 2, HGNC:29869) is a protein-coding gene on chromosome 19p13.3, encoding SHC-transforming protein 2 (P98077). Signaling adapter that couples activated growth factor receptors to signaling pathway in neurons.

Predicted to enable receptor tyrosine kinase binding activity. Predicted to be involved in cell surface receptor protein tyrosine kinase signaling pathway. Predicted to be located in cytosol. Predicted to be active in plasma membrane.

Source: NCBI Gene 25759 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 161 total
• Druggable target: yes
• MANE Select transcript: NM_012435

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29869
Approved symbol	SHC2
Name	SHC adaptor protein 2
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SLI, SCK, SHCB
Ensembl gene	ENSG00000129946
Ensembl biotype	protein_coding
OMIM	605217
Entrez	25759

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000264554, ENST00000587423, ENST00000588376, ENST00000590113, ENST00000590170, ENST00000590222, ENST00000939515, ENST00000945164, ENST00000945165, ENST00000945166, ENST00000945167, ENST00000945168, ENST00000945169, ENST00000945170, ENST00000945171, ENST00000945172, ENST00000945173, ENST00000945174, ENST00000945175

RefSeq mRNA: 2 — MANE Select: NM_012435 NM_001387056, NM_012435

CCDS: CCDS45891

Canonical transcript exons

ENST00000264554 — 13 exons

Exon	Start	End
ENSE00000910017	460529	461033
ENSE00000910018	440862	440932
ENSE00002844526	416589	417322
ENSE00003461316	434709	434865
ENSE00003570543	430684	430747
ENSE00003596875	425097	425231
ENSE00003600460	422146	422456
ENSE00003637007	438970	439030
ENSE00003643532	418923	419056
ENSE00003696469	436630	436683
ENSE00003701021	438718	438837
ENSE00003701454	436380	436431
ENSE00003701762	436165	436291

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 98.41.

FANTOM5 (CAGE): breadth broad, TPM avg 6.9273 / max 107.3630, expressed in 900 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177896	6.4802	877
177897	0.4472	276

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.41	gold quality
adenohypophysis	UBERON:0002196	97.69	gold quality
right lobe of liver	UBERON:0001114	96.88	gold quality
right uterine tube	UBERON:0001302	96.67	gold quality
mucosa of stomach	UBERON:0001199	96.63	gold quality
pituitary gland	UBERON:0000007	96.57	gold quality
apex of heart	UBERON:0002098	96.51	gold quality
right frontal lobe	UBERON:0002810	96.27	gold quality
left lobe of thyroid gland	UBERON:0001120	96.14	gold quality
right lobe of thyroid gland	UBERON:0001119	95.71	gold quality
amygdala	UBERON:0001876	95.20	gold quality
endocervix	UBERON:0000458	95.16	gold quality
cingulate cortex	UBERON:0003027	94.93	gold quality
anterior cingulate cortex	UBERON:0009835	94.85	gold quality
left uterine tube	UBERON:0001303	94.74	gold quality
thyroid gland	UBERON:0002046	94.49	gold quality
hypothalamus	UBERON:0001898	94.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.83	gold quality
body of stomach	UBERON:0001161	93.63	gold quality
nucleus accumbens	UBERON:0001882	93.48	gold quality
spleen	UBERON:0002106	93.35	gold quality
minor salivary gland	UBERON:0001830	93.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.42	gold quality
gall bladder	UBERON:0002110	92.38	gold quality
body of uterus	UBERON:0009853	92.33	gold quality
omental fat pad	UBERON:0010414	91.94	gold quality
peritoneum	UBERON:0002358	91.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.83	gold quality
ectocervix	UBERON:0012249	91.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.54

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• Data show that copy number loss of SHC2 strongly indicates a causal link to multiple system atrophy. (PMID:21658278)
• SHC2 gene deletions underlie few, if any, cases of well-characterized multiple system atrophy in the US population. (PMID:24170347)
• Sck was identified as a novel molecule indispensable for CD95’s activation of the PI3K and MAPK pathways and induction of cell cycle progression in pancreatic ductal adenocarcinoma. (PMID:25613377)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

SHC-transforming protein 2 — P98077 (reviewed: P98077)

Alternative names: Protein Sck, SHC-transforming protein B, Src homology 2 domain-containing-transforming protein C2

All UniProt accessions (3): P98077, K7EKS8, K7ENB2

UniProt curated annotations — full annotation on UniProt →

Function. Signaling adapter that couples activated growth factor receptors to signaling pathway in neurons. Involved in the signal transduction pathways of neurotrophin-activated Trk receptors in cortical neurons.

Subunit / interactions. Interacts with the Trk receptors in a phosphotyrosine-dependent manner and MEGF12. Once activated, binds to GRB2.

Tissue specificity. Expressed in brain. Expressed at high level in the hypothalamus and at low level in the caudate nucleus.

Post-translational modifications. Phosphorylated on tyrosines by the Trk receptors.

Domain organisation. The PID domain mediates binding to the TrkA receptor.

Miscellaneous. PubMed:15057824 has shown that SHC2 is poorly phosphorylated by the Trk receptors, in opposite to PubMed:12006576.

RefSeq proteins (2): NP_001373985, NP_036567* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR006019	PID_Shc-like	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035676	SHC_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051235	CEP152/SHC-Transforming	Family

Pfam: PF00017, PF00640

UniProt features (20 total): sequence conflict 9, region of interest 4, modified residue 3, domain 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98077-F1	63.12	0.18

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 (3): 414, 338, 339

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-167044	Signalling to RAS
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-187687	Signalling to ERKs
R-HSA-194138	Signaling by VEGF
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 77 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, BROWNE_HCMV_INFECTION_48HR_DN, REACTOME_SIGNALLING_TO_RAS, KEGG_ERBB_SIGNALING_PATHWAY, MODULE_301, REACTOME_SIGNALLING_TO_ERKS, MODULE_188, GOMF_SIGNALING_RECEPTOR_BINDING, KEGG_NEUROTROPHIN_SIGNALING_PATHWAY, KEGG_VEGF_SIGNALING_PATHWAY, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY, chr19p13, KEGG_INSULIN_SIGNALING_PATHWAY, KEGG_GLIOMA

GO Biological Process (2): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), intracellular signal transduction (GO:0035556)

GO Molecular Function (2): receptor tyrosine kinase binding (GO:0030971), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Signal Transduction	2
Signalling to ERKs	1
Signaling by VEGF	1
MAPK1/MAPK3 signaling	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
MAPK family signaling cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
enzyme-linked receptor protein signaling pathway	1
intracellular anatomical structure	1
signal transduction	1
signaling receptor binding	1
protein tyrosine kinase binding	1
binding	1
cytoplasm	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

832 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHC2	PEAR1	Q5VY43	777
SHC2	SORBS2	O94875	710
SHC2	SLC50A1	Q9BRV3	698
SHC2	SRC	P12931	620
SHC2	NTRK2	Q16620	617
SHC2	NTRK1	P04629	567
SHC2	CRK	P46108	567
SHC2	CBL	P22681	559
SHC2	EGFR	P00533	530
SHC2	CIMAP1D	Q3SX64	528
SHC2	RRN3	Q9NYV6	480
SHC2	GAB2	Q9UQC2	463
SHC2	EGF	P01133	459
SHC2	FGD2	Q7Z6J4	443
SHC2	ROBO1	Q9Y6N7	438

IntAct

27 interactions, top by confidence:

A	B	Type	Score
ERRFI1	EGFR	psi-mi:“MI:0914”(association)	0.930
SHC1	AP2A1	psi-mi:“MI:0914”(association)	0.730
SHC2	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
SHC2	EGFR	psi-mi:“MI:0407”(direct interaction)	0.440
SHC2	KIT	psi-mi:“MI:0407”(direct interaction)	0.440
SHC2	MET	psi-mi:“MI:0407”(direct interaction)	0.440
SHC2	Ntrk1	psi-mi:“MI:0915”(physical association)	0.400
SHC1	AP2A1	psi-mi:“MI:0914”(association)	0.350
SHC2	Iars2	psi-mi:“MI:0914”(association)	0.350
SHC2	Vps13d	psi-mi:“MI:0914”(association)	0.350
SHC2	AP2A1	psi-mi:“MI:0914”(association)	0.350
SHC2	VWA8	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
RIN3	SHC2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (49): SHC2 (Two-hybrid), SHC2 (Affinity Capture-Western), SHC2 (Reconstituted Complex), SHC2 (Two-hybrid), SHC2 (Two-hybrid), GRB2 (Affinity Capture-Western), EGFR (Affinity Capture-Western), SHC2 (Affinity Capture-MS), SHC2 (Affinity Capture-RNA), EGFR (Affinity Capture-Western), SHC2 (Affinity Capture-Western), SHC2 (Reconstituted Complex), SHC2 (Reconstituted Complex), SHC2 (Reconstituted Complex), SHC2 (Reconstituted Complex)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A2R8YCJ5, A2A699, A2AEV7, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NL88, A8MVW0, A9JSM3, B2RU40, B8ZZ34, C9JH25, D4A9R4, J3QNX5, P0CG09, P98077, Q0VD38, Q14761, Q17QH7, Q29RK8, Q2KJ18, Q2M3V2, Q3SX20, Q5BJT1, Q5HZJ5, Q5RKR3, Q5T442, Q64697, Q69YZ2, Q6PB97, Q6PCT2, Q6UXK2, Q6ZMQ8, Q6ZVH7, Q6ZW31, Q80XF7, Q8BLS7

Diamond homologs: D3ZAZ5, O14796, O70142, O70143, O75791, O75815, O88900, P00519, P00520, P00521, P00522, P00530, P00541, P00542, P00543, P07332, P10447, P14238, P16591, P16879, P29350, P29351, P29353, P29355, P42684, P46109, P47941, P53356, P62993, P62994, P70451, P81718, P87379, P98077, P98083, Q07883, Q08012, Q0IIE2, Q13588, Q4JIM5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EGFR	up-regulates	SHC2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of MAPK cascade	5	36.6×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	135
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3316 predictions. Top by Δscore:

Variant	Effect	Δscore
19:419052:CGTAC:C	acceptor_gain	1.0000
19:419057:CTGC:C	acceptor_loss	1.0000
19:419058:T:A	acceptor_loss	1.0000
19:425095:A:AC	donor_gain	1.0000
19:425096:C:CC	donor_gain	1.0000
19:425096:CG:C	donor_gain	1.0000
19:425110:AT:A	donor_gain	1.0000
19:425111:T:TA	donor_gain	1.0000
19:434704:CTGA:C	donor_loss	1.0000
19:434705:TGAC:T	donor_loss	1.0000
19:434706:GACC:G	donor_loss	1.0000
19:434707:A:C	donor_loss	1.0000
19:434708:C:CG	donor_loss	1.0000
19:437166:A:AC	donor_gain	1.0000
19:437167:C:CC	donor_gain	1.0000
19:437171:T:C	donor_gain	1.0000
19:438713:CCCA:C	donor_loss	1.0000
19:438715:CAC:C	donor_loss	1.0000
19:438716:A:T	donor_loss	1.0000
19:438966:TCA:T	donor_loss	1.0000
19:438967:CACCT:C	donor_loss	1.0000
19:438968:A:AC	donor_gain	1.0000
19:438968:ACCTT:A	donor_loss	1.0000
19:438969:C:A	donor_loss	1.0000
19:438969:C:CC	donor_gain	1.0000
19:440928:ATGTA:A	acceptor_gain	1.0000
19:440929:TGTA:T	acceptor_gain	1.0000
19:440931:TA:T	acceptor_gain	1.0000
19:440933:C:CC	acceptor_gain	1.0000
19:418936:C:CA	donor_gain	0.9900

AlphaMissense

3742 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:418983:A:T	I565N	1.000
19:419016:A:G	L554P	1.000
19:419033:A:C	F548L	1.000
19:419033:A:T	F548L	1.000
19:419035:A:G	F548L	1.000
19:422165:A:G	L534P	1.000
19:422165:A:T	L534H	1.000
19:422171:A:G	L532P	1.000
19:422204:A:G	L521P	1.000
19:422204:A:T	L521H	1.000
19:422207:A:T	V520D	1.000
19:422245:G:C	F507L	1.000
19:422245:G:T	F507L	1.000
19:422246:A:G	F507S	1.000
19:422247:A:G	F507L	1.000
19:436219:A:G	L300P	1.000
19:436224:G:C	F298L	1.000
19:436224:G:T	F298L	1.000
19:436226:A:G	F298L	1.000
19:436289:A:G	C277R	1.000
19:436406:A:T	V267D	1.000
19:436410:A:C	Y266D	1.000
19:436412:G:T	A265D	1.000
19:436648:G:C	F252L	1.000
19:436648:G:T	F252L	1.000
19:436649:A:C	F252C	1.000
19:436649:A:G	F252S	1.000
19:436650:A:G	F252L	1.000
19:439026:C:G	A182P	1.000
19:440878:G:T	R175S	1.000

dbSNP variants (sampled 300 via entrez): RS1000027041 (19:416157 C>A), RS1000055753 (19:454214 C>T), RS1000111412 (19:442205 T>C), RS1000142206 (19:461923 C>A,G), RS1000232414 (19:457935 G>A), RS1000233315 (19:443243 T>C), RS1000241632 (19:426204 G>A), RS1000291559 (19:438323 G>A), RS1000320920 (19:438520 C>A,T), RS1000353515 (19:430252 C>T), RS1000565076 (19:456916 C>A,T), RS1000638903 (19:429324 C>T), RS1000683901 (19:439235 G>C,T), RS1000917448 (19:428319 G>A), RS1000979142 (19:425302 G>A)

Disease associations

OMIM: gene MIM:605217 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007483_30	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-06
GCST007487_33	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3299 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	2
Valproic Acid	increases methylation, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects methylation	1
abrine	increases expression	1
asparanin A	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	decreases expression, affects cotreatment	1
Estradiol	decreases expression	1
Glucose	decreases expression	1
Lead	increases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Testosterone	increases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL873005	Binding	Inhibition of binding to SH2 domain of SHC-PTB	Potent antagonists of the SH2 domain of Grb2: optimization of the X+1 position of 3-amino-Z-Tyr(PO3H2)-X+1-Asn-NH2. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2F7	Abcam HeLa SHC2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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