SHC4

Summary

SHC4 (SHC adaptor protein 4, HGNC:16743) is a protein-coding gene on chromosome 15q21.1, encoding SHC-transforming protein 4 (Q6S5L8). Activates both Ras-dependent and Ras-independent migratory pathways in melanomas.

Predicted to enable receptor tyrosine kinase binding activity. Predicted to be involved in cell surface receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within several processes, including apoptotic process; positive regulation of cell population proliferation; and stem cell differentiation. Predicted to be located in postsynaptic membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 399694 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 94 total
• MANE Select transcript: NM_203349

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16743
Approved symbol	SHC4
Name	SHC adaptor protein 4
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Aliases	RaLP, SHCD
Ensembl gene	ENSG00000185634
Ensembl biotype	protein_coding
OMIM	617372
Entrez	399694

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000332408, ENST00000396535, ENST00000537958, ENST00000557797, ENST00000558220, ENST00000559289

RefSeq mRNA: 1 — MANE Select: NM_203349 NM_203349

CCDS: CCDS10130

Canonical transcript exons

ENST00000332408 — 12 exons

Exon	Start	End
ENSE00001305651	48867818	48867869
ENSE00001306033	48924879	48924949
ENSE00001309067	48884248	48884367
ENSE00001316485	48962431	48963919
ENSE00001323942	48851188	48851248
ENSE00001325906	48857692	48857815
ENSE00001327954	48834769	48835022
ENSE00001328242	48890748	48890811
ENSE00001875640	48823741	48826126
ENSE00003536525	48843409	48843588
ENSE00003617624	48872089	48872142
ENSE00003783957	48855953	48856124

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 92.72.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5502 / max 109.8426, expressed in 650 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149792	1.3824	298
149791	0.4655	148
149801	0.2172	107
149798	0.1871	90
149802	0.1421	76
149800	0.1245	53
149797	0.0200	8
149799	0.0113	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.72	gold quality
trigeminal ganglion	UBERON:0001675	92.38	gold quality
dorsal root ganglion	UBERON:0000044	91.66	gold quality
corpus callosum	UBERON:0002336	88.63	gold quality
tibial nerve	UBERON:0001323	87.61	gold quality
sural nerve	UBERON:0015488	86.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.61	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.77	gold quality
spinal cord	UBERON:0002240	82.61	gold quality
left coronary artery	UBERON:0001626	81.07	gold quality
coronary artery	UBERON:0001621	80.56	gold quality
right coronary artery	UBERON:0001625	80.56	gold quality
substantia nigra	UBERON:0002038	79.71	gold quality
inferior vagus X ganglion	UBERON:0005363	79.61	gold quality
endothelial cell	CL:0000115	79.59	gold quality
Brodmann (1909) area 46	UBERON:0006483	78.91	gold quality
putamen	UBERON:0001874	78.87	gold quality
midbrain	UBERON:0001891	78.50	gold quality
amygdala	UBERON:0001876	78.32	gold quality
stromal cell of endometrium	CL:0002255	78.31	gold quality
Ammon’s horn	UBERON:0001954	78.19	gold quality
caudate nucleus	UBERON:0001873	77.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.34	gold quality
tibia	UBERON:0000979	77.30	gold quality
thoracic aorta	UBERON:0001515	76.76	gold quality
ascending aorta	UBERON:0001496	76.71	gold quality
pons	UBERON:0000988	76.33	gold quality
descending thoracic aorta	UBERON:0002345	76.33	gold quality
pancreatic ductal cell	CL:0002079	76.31	silver quality
Brodmann (1909) area 9	UBERON:0013540	75.68	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

136 targeting SHC4, 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-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1271-5P	99.91	71.99	1972

Literature-anchored findings (GeneRIF, showing 9)

• A new member of the Shc family of docking proteins is characterised, which may mediate a specific aspect of signaling downstream of the MuSK receptor. (PMID:17452444)
• ShcD binds to TrkC in a kinase-activity-dependent manner through its PTB and SH2 domains. (PMID:20078941)
• ShcD interacts with TrkB in a kinase-activity-dependent manner. (PMID:20663410)
• ShcD can exist within the nucleus, and its CH2 domain has a critical role in nuclear export of ShcD. (PMID:24036217)
• The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor. (PMID:24430869)
• ShcD binds to active Ret, TrkA, and TrkB neurotrophic factor receptors predominantly via its phosphotyrosine-binding (PTB) domain. (PMID:28213521)
• ShcD appears to possess several molecular permutations that actively govern the EGFR, which may have implications in development and disease. (PMID:28724758)
• Adaptor Protein ShcD/SHC4 Interacts with Tie2 Receptor to Synergistically Promote Glioma Cell Invasion. (PMID:33495401)
• SHC4 orchestrates beta-catenin pathway-mediated metastasis in triple-negative breast cancer by promoting Src kinase autophosphorylation. (PMID:38052369)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Shc4	ENSMUSG00000035109
rattus_norvegicus	Shc4	ENSRNOG00000037134
drosophila_melanogaster	Shc	FBGN0015296

Paralogs (3): CEP152 (ENSG00000103995), SHC3 (ENSG00000148082), SHC1 (ENSG00000160691)

Protein

Protein identifiers

SHC-transforming protein 4 — Q6S5L8 (reviewed: Q6S5L8)

Alternative names: Rai-like protein, SHC-transforming protein D, Src homology 2 domain-containing-transforming protein C4

All UniProt accessions (4): F5H5M1, Q6S5L8, H0YLU6, H0YLZ2

UniProt curated annotations — full annotation on UniProt →

Function. Activates both Ras-dependent and Ras-independent migratory pathways in melanomas. Contributes to the early phases of agrin-induced tyrosine phosphorylation of CHRNB1.

Subunit / interactions. Interacts (via PID domain) with phosphorylated MUSK (via NPXY motif); undergoes tyrosine phosphorylation downstream of activated MUSK. Interacts with GRB2; the interaction is dependent of Tyr-424 phosphorylation and increased by EGF.

Subcellular location. Postsynaptic cell membrane.

Tissue specificity. Only expressed in melanomas. Weakly expressed in normal melanocytes and benign nevi. Highly expressed at the transition from radial growth phase to vertical growth phase and metastatic melanomas, when tumor cells acquire migratory competence and invasive potential.

Post-translational modifications. Phosphorylated; the phosphorylation is enhanced by EGF. Phosphorylation at Tyr-424 is required for the interaction with GRB2.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6S5L8-1	1	yes
Q6S5L8-2	2

RefSeq proteins (1): NP_976224* (*=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 (25 total): mutagenesis site 7, region of interest 5, sequence variant 4, compositionally biased region 3, domain 2, splice variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6S5L8-F1	59.12	0.16

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 (1): 424

Mutagenesis-validated functional residues (7):

Position	Phenotype
315	phosphorylation is markedly decreased. completely reduces the phosphorylation and interaction with musk; when associated
374–375	remains phosphorylated. contains a residual phosphorylation; when associated with f-465. retains the ability to bind mus
403	completely abolishes the phosphorylation in presence of musk; when associated with 374-f-f-375; f-413; f-424 and f-465.
413	completely abolishes the phosphorylation in presence of musk; when associated with 374-f-f-375; f-403; f-424 and f-465.
424	significantly decreased grb2 interaction. reduced the phosphorylation in presence of musk; when associated with 374-f-f-
465	remains phosphorylated. contains a residual phosphorylation; when associated with 374-f-f-375. reduced the phosphorylati
549	completely reduces the phosphorylation and interaction with musk; when associated with q-315.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 132 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, BENPORATH_ES_WITH_H3K27ME3, PEREZ_TP63_TARGETS, GTGCCTT_MIR506, KEGG_ERBB_SIGNALING_PATHWAY, GGCAGTG_MIR3243P, PEREZ_TP53_AND_TP63_TARGETS, GOBP_STEM_CELL_DIFFERENTIATION, GOMF_SIGNALING_RECEPTOR_BINDING, KEGG_NEUROTROPHIN_SIGNALING_PATHWAY, GOCC_POSTSYNAPSE, GOCC_SYNAPSE, GOCC_POSTSYNAPTIC_MEMBRANE, GOCC_PLASMA_MEMBRANE_REGION, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY

GO Biological Process (6): apoptotic process (GO:0006915), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of cell population proliferation (GO:0008284), regulation of gene expression (GO:0010468), intracellular signal transduction (GO:0035556), stem cell differentiation (GO:0048863)

GO Molecular Function (3): protein domain specific binding (GO:0019904), receptor tyrosine kinase binding (GO:0030971), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), postsynaptic membrane (GO:0045211), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
enzyme-linked receptor protein signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
intracellular anatomical structure	1
signal transduction	1
cell differentiation	1
protein binding	1
signaling receptor binding	1
protein tyrosine kinase binding	1
binding	1
membrane	1
cell periphery	1
synaptic membrane	1
postsynapse	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

576 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHC4	PFDN4	Q9NQP4	587
SHC4	CHORDC1	Q9UHD1	580
SHC4	MUSK	O15146	502
SHC4	BRAF	P15056	474
SHC4	FLT4	P35916	458
SHC4	IGF1R	P08069	455
SHC4	ALK	Q9UM73	451
SHC4	NRAS	P01111	428
SHC4	SRM	P19623	386
SHC4	EID1	Q9Y6B2	349
SHC4	GRB2	P29354	341
SHC4	PPP2R2C	Q9Y2T4	332
SHC4	ARHGAP5	Q13017	330
SHC4	RHPN1	Q8TCX5	328
SHC4	LAMB2	P55268	316

IntAct

14 interactions, top by confidence:

A	B	Type	Score
NUAK2	PPP1R12A	psi-mi:“MI:0914”(association)	0.640
EGFR	SHC4	psi-mi:“MI:0915”(physical association)	0.630
SHC4	EGFR	psi-mi:“MI:0915”(physical association)	0.630
SHC4	AR	psi-mi:“MI:0407”(direct interaction)	0.440
SHC4	KIT	psi-mi:“MI:0407”(direct interaction)	0.440
SHC4	MET	psi-mi:“MI:0407”(direct interaction)	0.440
ALK	SHC4	psi-mi:“MI:0915”(physical association)	0.370
SHC4	CHUK	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): SHC4 (Two-hybrid), SHC4 (PCA), SHC4 (Affinity Capture-Luminescence), EGFR (Affinity Capture-Western), GRB2 (Affinity Capture-Western), EGFR (Reconstituted Complex), NBEA (Affinity Capture-MS), GAREM (Affinity Capture-MS), CHUK (Affinity Capture-MS), AMD1 (Affinity Capture-MS), SHC3 (Affinity Capture-MS), SHC4 (Affinity Capture-Western), SHC4 (Affinity Capture-Western), SHC4 (Co-localization), NTRK2 (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: 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
ERK1/2	“down-regulates activity”	SHC4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	87
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2207 predictions. Top by Δscore:

Variant	Effect	Δscore
15:48843407:A:AC	donor_gain	1.0000
15:48843407:ACTT:A	donor_gain	1.0000
15:48843408:C:CC	donor_gain	1.0000
15:48843408:CTTC:C	donor_gain	1.0000
15:48855967:TTTC:T	donor_gain	1.0000
15:48856121:CTCA:C	acceptor_gain	1.0000
15:48856123:CA:C	acceptor_gain	1.0000
15:48856125:C:CC	acceptor_gain	1.0000
15:48857688:TGA:T	donor_loss	1.0000
15:48857689:GAC:G	donor_loss	1.0000
15:48857690:A:AG	donor_loss	1.0000
15:48857691:CCT:C	donor_loss	1.0000
15:48857812:CAGG:C	acceptor_gain	1.0000
15:48857813:AGG:A	acceptor_gain	1.0000
15:48857814:GG:G	acceptor_gain	1.0000
15:48857816:C:CC	acceptor_gain	1.0000
15:48857828:A:AC	acceptor_gain	1.0000
15:48857828:A:C	acceptor_gain	1.0000
15:48872087:A:AC	donor_gain	1.0000
15:48872088:C:CC	donor_gain	1.0000
15:48884370:T:C	acceptor_gain	1.0000
15:48884370:T:TC	acceptor_gain	1.0000
15:48884376:A:AC	acceptor_gain	1.0000
15:48884377:T:C	acceptor_gain	1.0000
15:48884377:T:TC	acceptor_gain	1.0000
15:48922292:CGAG:C	acceptor_gain	1.0000
15:48826124:CACCT:C	acceptor_gain	0.9900
15:48826128:T:C	acceptor_gain	0.9900
15:48826128:T:TC	acceptor_gain	0.9900
15:48835023:C:CC	acceptor_gain	0.9900

AlphaMissense

4135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:48857748:A:C	F338L	1.000
15:48857748:A:T	F338L	1.000
15:48857750:A:G	F338L	1.000
15:48872107:A:C	F292L	1.000
15:48872107:A:T	F292L	1.000
15:48872109:A:G	F292L	1.000
15:48826053:A:T	I604N	0.999
15:48826075:G:C	H597D	0.999
15:48826086:A:G	L593P	0.999
15:48826103:A:C	F587L	0.999
15:48826103:A:T	F587L	0.999
15:48826105:A:G	F587L	0.999
15:48834794:A:G	L571P	0.999
15:48834823:A:C	S561R	0.999
15:48834823:A:T	S561R	0.999
15:48834825:T:G	S561R	0.999
15:48834827:A:G	L560P	0.999
15:48834827:A:T	L560Q	0.999
15:48834860:C:G	R549P	0.999
15:48834863:A:T	V548D	0.999
15:48857806:A:T	I319K	0.999
15:48857811:A:C	C317W	0.999
15:48857813:A:G	C317R	0.999
15:48867838:T:A	K309I	0.999
15:48867841:G:T	A308D	0.999
15:48867842:C:G	A308P	0.999
15:48867848:A:C	Y306D	0.999
15:48867850:G:T	A305D	0.999
15:48867853:A:T	V304D	0.999
15:48872105:G:T	A293D	0.999

dbSNP variants (sampled 300 via entrez): RS1000008272 (15:48837483 C>G,T), RS1000023373 (15:48965779 G>A,T), RS1000034606 (15:48923449 C>T), RS1000051412 (15:48894480 A>G), RS1000058546 (15:48901385 C>G), RS1000064678 (15:48880044 G>A), RS1000086121 (15:48849880 A>G), RS1000130459 (15:48914490 T>C,G), RS1000142364 (15:48919225 G>A,C), RS1000159316 (15:48831756 T>C), RS1000199260 (15:48863879 C>A,G,T), RS1000203987 (15:48961162 C>T), RS1000215063 (15:48919574 C>T), RS1000223900 (15:48874172 GAACA>G), RS1000241202 (15:48869707 TA>T,TAA)

Disease associations

OMIM: gene MIM:617372 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001083_2	Major depressive disorder	2.000000e-06
GCST001644_7	Eating disorders	6.000000e-06
GCST002936_27	Cadmium levels	1.000000e-06
GCST005108_3	Major depressive disorder	4.000000e-06
GCST007741_11	Iris color (b* coordinate)	9.000000e-06
GCST009252_3	Skin aging measurement	2.000000e-08
GCST009252_5	Skin aging measurement	9.000000e-10
GCST012301_6	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009764	eye colour measurement
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, decreases methylation, increases expression	4
Air Pollutants	increases abundance, decreases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nickel	decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression, affects splicing	1
perfluorooctanoic acid	increases expression	1
ferrous chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Zoledronic Acid	decreases expression	1
Glyphosate	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Doxorubicin	increases expression	1
Drugs, Chinese Herbal	increases expression	1
Formaldehyde	increases expression	1
Lucanthone	increases expression	1
Methyl Methanesulfonate	increases expression	1
Naphthoquinones	increases expression	1
Progesterone	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2F9	Abcam HeLa SHC4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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