SHC4_HUMAN
ID SHC4_HUMAN Reviewed; 630 AA.
AC Q6S5L8; Q6UXQ3; Q8IYW3;
DT 20-MAY-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 149.
DE RecName: Full=SHC-transforming protein 4;
DE AltName: Full=Rai-like protein;
DE Short=RaLP;
DE AltName: Full=SHC-transforming protein D;
DE Short=hShcD;
DE AltName: Full=Src homology 2 domain-containing-transforming protein C4;
DE Short=SH2 domain protein C4;
GN Name=SHC4; Synonyms=SHCD; ORFNames=UNQ6438/PRO21364;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=17409413; DOI=10.1158/0008-5472.can-06-2301;
RA Fagiani E., Giardina G., Luzi L., Cesaroni M., Quarto M., Capra M.,
RA Germano G., Bono M., Capillo M., Pelicci P., Lanfrancone L.;
RT "RaLP, a new member of the Src homology and collagen family, regulates cell
RT migration and tumor growth of metastatic melanomas.";
RL Cancer Res. 67:3064-3073(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS ASP-52;
RP GLU-244 AND GLY-447.
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH MUSK AND GRB2, PHOSPHORYLATION AT TYR-424, AND MUTAGENESIS
RP OF ARG-315; 374-TYR-TYR-375; TYR-403; TYR-413; TYR-424; TYR-465 AND
RP ARG-549.
RX PubMed=17452444; DOI=10.1128/mcb.00184-07;
RA Jones N., Hardy W.R., Friese M.B., Jorgensen C., Smith M.J., Woody N.M.,
RA Burden S.J., Pawson T.;
RT "Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with
RT muscle-specific kinase.";
RL Mol. Cell. Biol. 27:4759-4773(2007).
CC -!- FUNCTION: Activates both Ras-dependent and Ras-independent migratory
CC pathways in melanomas. Contributes to the early phases of agrin-induced
CC tyrosine phosphorylation of CHRNB1. {ECO:0000269|PubMed:17409413}.
CC -!- SUBUNIT: Interacts (via PID domain) with phosphorylated MUSK (via NPXY
CC motif); undergoes tyrosine phosphorylation downstream of activated
CC MUSK. Interacts with GRB2; the interaction is dependent of Tyr-424
CC phosphorylation and increased by EGF. {ECO:0000269|PubMed:17452444}.
CC -!- INTERACTION:
CC Q6S5L8; P10275: AR; NbExp=3; IntAct=EBI-9453524, EBI-608057;
CC Q6S5L8; P00533: EGFR; NbExp=3; IntAct=EBI-9453524, EBI-297353;
CC Q6S5L8; P08581: MET; NbExp=3; IntAct=EBI-9453524, EBI-1039152;
CC -!- SUBCELLULAR LOCATION: Postsynaptic cell membrane. Note=Colocalized with
CC MUSK at the neuromuscular junction. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6S5L8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6S5L8-2; Sequence=VSP_033965, VSP_033966;
CC -!- TISSUE SPECIFICITY: Only expressed in melanomas. Weakly expressed in
CC normal melanocytes and benign nevi. Highly expressed at the transition
CC from radial growth phase to vertical growth phase and metastatic
CC melanomas, when tumor cells acquire migratory competence and invasive
CC potential. {ECO:0000269|PubMed:17409413}.
CC -!- PTM: Phosphorylated; the phosphorylation is enhanced by EGF.
CC Phosphorylation at Tyr-424 is required for the interaction with GRB2.
CC {ECO:0000269|PubMed:17452444}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SHC4ID44503ch15q21.html";
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DR EMBL; AY464565; AAR19363.1; -; mRNA.
DR EMBL; AY358250; AAQ88617.1; -; mRNA.
DR EMBL; BC033907; AAH33907.1; -; mRNA.
DR CCDS; CCDS10130.1; -. [Q6S5L8-1]
DR RefSeq; NP_976224.3; NM_203349.3. [Q6S5L8-1]
DR AlphaFoldDB; Q6S5L8; -.
DR SMR; Q6S5L8; -.
DR BioGRID; 134386; 27.
DR IntAct; Q6S5L8; 4.
DR STRING; 9606.ENSP00000329668; -.
DR iPTMnet; Q6S5L8; -.
DR PhosphoSitePlus; Q6S5L8; -.
DR BioMuta; SHC4; -.
DR DMDM; 74722804; -.
DR EPD; Q6S5L8; -.
DR jPOST; Q6S5L8; -.
DR MassIVE; Q6S5L8; -.
DR MaxQB; Q6S5L8; -.
DR PaxDb; Q6S5L8; -.
DR PeptideAtlas; Q6S5L8; -.
DR PRIDE; Q6S5L8; -.
DR Antibodypedia; 24605; 175 antibodies from 30 providers.
DR DNASU; 399694; -.
DR Ensembl; ENST00000332408.9; ENSP00000329668.4; ENSG00000185634.12. [Q6S5L8-1]
DR Ensembl; ENST00000396535.7; ENSP00000379786.3; ENSG00000185634.12. [Q6S5L8-2]
DR GeneID; 399694; -.
DR KEGG; hsa:399694; -.
DR MANE-Select; ENST00000332408.9; ENSP00000329668.4; NM_203349.4; NP_976224.3.
DR UCSC; uc001zxb.2; human. [Q6S5L8-1]
DR CTD; 399694; -.
DR DisGeNET; 399694; -.
DR GeneCards; SHC4; -.
DR HGNC; HGNC:16743; SHC4.
DR HPA; ENSG00000185634; Tissue enhanced (brain, testis).
DR MIM; 617372; gene.
DR neXtProt; NX_Q6S5L8; -.
DR OpenTargets; ENSG00000185634; -.
DR PharmGKB; PA142670917; -.
DR VEuPathDB; HostDB:ENSG00000185634; -.
DR eggNOG; KOG3697; Eukaryota.
DR GeneTree; ENSGT00950000182870; -.
DR HOGENOM; CLU_029532_2_0_1; -.
DR InParanoid; Q6S5L8; -.
DR OMA; LMNIDNQ; -.
DR OrthoDB; 1351843at2759; -.
DR PhylomeDB; Q6S5L8; -.
DR TreeFam; TF315807; -.
DR PathwayCommons; Q6S5L8; -.
DR SignaLink; Q6S5L8; -.
DR BioGRID-ORCS; 399694; 4 hits in 1067 CRISPR screens.
DR ChiTaRS; SHC4; human.
DR GenomeRNAi; 399694; -.
DR Pharos; Q6S5L8; Tbio.
DR PRO; PR:Q6S5L8; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q6S5L8; protein.
DR Bgee; ENSG00000185634; Expressed in buccal mucosa cell and 132 other tissues.
DR ExpressionAtlas; Q6S5L8; baseline and differential.
DR Genevisible; Q6S5L8; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl.
DR GO; GO:0019901; F:protein kinase binding; IBA:GO_Central.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:0048863; P:stem cell differentiation; IEA:Ensembl.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR CDD; cd01209; PTB_Shc; 1.
DR CDD; cd09925; SH2_SHC; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR006019; PID_Shc-like.
DR InterPro; IPR006020; PTB/PI_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR029596; SHC4.
DR InterPro; IPR035676; SHC_SH2.
DR PANTHER; PTHR10337:SF12; PTHR10337:SF12; 1.
DR Pfam; PF00640; PID; 1.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00629; SHCPIDOMAIN.
DR SMART; SM00462; PTB; 1.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS01179; PID; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Membrane; Phosphoprotein;
KW Postsynaptic cell membrane; Reference proteome; SH2 domain; Synapse.
FT CHAIN 1..630
FT /note="SHC-transforming protein 4"
FT /id="PRO_0000337200"
FT DOMAIN 186..369
FT /note="PID"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT DOMAIN 526..617
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT REGION 1..185
FT /note="CH2"
FT REGION 39..80
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 118..150
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 370..525
FT /note="CH1"
FT REGION 471..514
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 39..53
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 124..145
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 471..487
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 424
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:17452444"
FT VAR_SEQ 1..243
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12975309"
FT /id="VSP_033965"
FT VAR_SEQ 244..280
FT /note="KFLSTVLGKSNLQFSGMNIKLTISTCSLTLMNLDNQQ -> MLPALEHWIPK
FT FFSFRTRTGSPLSLACRQPIVGPCDH (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12975309"
FT /id="VSP_033966"
FT VARIANT 52
FT /note="N -> D (in dbSNP:rs17856991)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_043672"
FT VARIANT 244
FT /note="K -> E (in dbSNP:rs17856990)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_043673"
FT VARIANT 400
FT /note="Q -> H (in dbSNP:rs16961728)"
FT /id="VAR_043674"
FT VARIANT 447
FT /note="D -> G (in dbSNP:rs17856992)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_043675"
FT MUTAGEN 315
FT /note="R->Q: Phosphorylation is markedly decreased.
FT Completely reduces the phosphorylation and interaction with
FT MUSK; when associated with K-549."
FT /evidence="ECO:0000269|PubMed:17452444"
FT MUTAGEN 374..375
FT /note="YY->F: Remains phosphorylated. Contains a residual
FT phosphorylation; when associated with F-465. Retains the
FT ability to bind MUSK. Reduced the phosphorylation in
FT presence of MUSK; when associated with F-424 and F-465.
FT Completely abolishes the phosphorylation in presence of
FT MUSK; when associated with F-403; F-413; F-424 and F-465.
FT Retains the ability to bind MUSK; when associated with F-
FT 465. Retains the ability to bind MUSK; when associated with
FT F-424 and F-465. Retains the ability to bind MUSK; when
FT associated with F-403; F-413; F-424 and F-465."
FT /evidence="ECO:0000269|PubMed:17452444"
FT MUTAGEN 403
FT /note="Y->F: Completely abolishes the phosphorylation in
FT presence of MUSK; when associated with 374-F-F-375; F-413;
FT F-424 and F-465."
FT /evidence="ECO:0000269|PubMed:17452444"
FT MUTAGEN 413
FT /note="Y->F: Completely abolishes the phosphorylation in
FT presence of MUSK; when associated with 374-F-F-375; F-403;
FT F-424 and F-465."
FT /evidence="ECO:0000269|PubMed:17452444"
FT MUTAGEN 424
FT /note="Y->F: Significantly decreased GRB2 interaction.
FT Reduced the phosphorylation in presence of MUSK; when
FT associated with 374-F-F-375 and F-465. Completely abolishes
FT the phosphorylation in presence of MUSK; when associated
FT with 374-F-F-375; F-403; F-413 and F-465."
FT /evidence="ECO:0000269|PubMed:17452444"
FT MUTAGEN 465
FT /note="Y->F: Remains phosphorylated. Contains a residual
FT phosphorylation; when associated with 374-F-F-375. Reduced
FT the phosphorylation in presence of MUSK; when associated
FT with 374-F-F-375 and 424. Completely abolishes the
FT phosphorylation in presence of MUSK; when associated with
FT 374-F-F-375; F-403; F-413 and F-424. Retains the ability to
FT bind MUSK. Retains the ability to bind MUSK; when
FT associated with 374-F-F-375. Retains the ability to bind
FT MUSK; when associated with 374-F-F-375 and F-424. Retains
FT the ability to bind MUSK; when associated with 374-F-F-375;
FT F-403; F-413 and F-424."
FT /evidence="ECO:0000269|PubMed:17452444"
FT MUTAGEN 549
FT /note="R->K: Completely reduces the phosphorylation and
FT interaction with MUSK; when associated with Q-315."
FT /evidence="ECO:0000269|PubMed:17452444"
SQ SEQUENCE 630 AA; 68785 MW; 504F3FCB894E2C59 CRC64;
MRERGQDSLA GLVLYVGLFG HPGMLHRAKY SRFRNESITS LDEGSSGGSV GNKGSPQPPH
PALAPHLPTE DATLPSQESP TPLCTLIPRM ASMKLANPAT LLSLKNFCLG TKEVPRLKLQ
ESRDPGSSGP SSPETSLSRS GTAPPPQQDL VGHRATALTP DSCPLPGPGE PTLRSRQDRH
FLQHLLGMGM NYCVRYMGCV EVLQSMRSLD FGMRTQVTRE AISRLCEAVP GANGAIKKRK
PPVKFLSTVL GKSNLQFSGM NIKLTISTCS LTLMNLDNQQ IIANHHMQSI SFASGGDPDT
TDYVAYVAKD PVNQRACHIL ECHNGMAQDV ISTIGQAFEL RFKQYLKNPS LNTSCESEEV
HIDSHAEERE DHEYYNEIPG KQPPVGGVSD MRIKVQATEQ MAYCPIQCEK LCYLPGNSKC
SSVYENCLEQ SRAIGNVHPR GVQSQRDTSL LKHTCRVDLF DDPCYINTQA LQSTPGSAGN
QRSAQPLGSP WHCGKAPETV QPGATAQPAS SHSLPHIKQQ LWSEECYHGK LSRKAAESLL
VKDGDFLVRE SATSPGQYVL SGLQGGQAKH LLLVDPEGKV RTKDHVFDNV GHLIRYHMDN
SLPIISSGSE VSLKQPVRKD NNPALLHSNK
