ID   SHC3_HUMAN              Reviewed;         594 AA.
AC   Q92529; Q5T7I7; Q8TAP2; Q9UCX5;
DT   29-MAR-2004, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1997, sequence version 1.
DT   24-JAN-2024, entry version 184.
DE   RecName: Full=SHC-transforming protein 3;
DE   AltName: Full=Neuronal Shc;
DE            Short=N-Shc;
DE   AltName: Full=Protein Rai;
DE   AltName: Full=SHC-transforming protein C;
DE   AltName: Full=Src homology 2 domain-containing-transforming protein C3;
DE            Short=SH2 domain protein C3;
GN   Name=SHC3; Synonyms=NSHC, SHCC;
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] (ISOFORMS P64 AND P52), AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=8808684;
RA   Nakamura T., Sanokawa R., Sasaki Y., Ayusawa D., Oishi M., Mori N.;
RT   "N-Shc: a neural-specific adapter molecule that mediates signaling from
RT   neurotrophin/Trk to Ras/MAPK pathway.";
RL   Oncogene 13:1111-1121(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P52).
RC   TISSUE=Fetal brain;
RX   PubMed=8760305;
RA   Pelicci G., Dente L., De Giuseppe A., Verducci-Galletti B., Giuli S.,
RA   Mele S., Vetriani C., Giorgio M., Pandolfi P.P., Cesareni G.,
RA   Pelicci P.-G.;
RT   "A family of Shc related proteins with conserved PTB, CH1 and SH2
RT   regions.";
RL   Oncogene 13:633-641(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164053; DOI=10.1038/nature02465;
RA   Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA   Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA   Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA   Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA   Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA   Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA   Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA   Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA   Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA   Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA   Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA   Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA   Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA   Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA   Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA   Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA   Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA   McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA   Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA   Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA   Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA   Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA   West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA   Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA   Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA   Dunham I.;
RT   "DNA sequence and analysis of human chromosome 9.";
RL   Nature 429:369-374(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P64).
RC   TISSUE=Brain;
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   [5]
RP   PHOSPHORYLATION, AND INTERACTION WITH THE TRK RECEPTORS.
RX   PubMed=12006576; DOI=10.1074/jbc.m111659200;
RA   Liu H.Y., Meakin S.O.;
RT   "ShcB and ShcC activation by the Trk family of receptor tyrosine kinases.";
RL   J. Biol. Chem. 277:26046-26056(2002).
CC   -!- FUNCTION: Signaling adapter that couples activated growth factor
CC       receptors to signaling pathway in neurons. Involved in the signal
CC       transduction pathways of neurotrophin-activated Trk receptors in
CC       cortical neurons.
CC   -!- SUBUNIT: Interacts with the Trk receptors in a phosphotyrosine-
CC       dependent manner. Once activated, binds to GRB2. Interacts with
CC       activated EGF receptors. {ECO:0000269|PubMed:12006576}.
CC   -!- INTERACTION:
CC       Q92529; Q9NXR5-2: ANKRD10; NbExp=3; IntAct=EBI-79084, EBI-12102070;
CC       Q92529; P05067: APP; NbExp=5; IntAct=EBI-79084, EBI-77613;
CC       Q92529; Q86U10: ASPG; NbExp=3; IntAct=EBI-79084, EBI-19946665;
CC       Q92529; Q96LC9: BMF; NbExp=3; IntAct=EBI-79084, EBI-3919268;
CC       Q92529; P24863: CCNC; NbExp=3; IntAct=EBI-79084, EBI-395261;
CC       Q92529; Q9BXL8: CDCA4; NbExp=3; IntAct=EBI-79084, EBI-1773949;
CC       Q92529; P40199: CEACAM6; NbExp=3; IntAct=EBI-79084, EBI-4314501;
CC       Q92529; Q7L5N1: COPS6; NbExp=3; IntAct=EBI-79084, EBI-486838;
CC       Q92529; Q8WUE5: CT55; NbExp=3; IntAct=EBI-79084, EBI-6873363;
CC       Q92529; Q7L591-3: DOK3; NbExp=3; IntAct=EBI-79084, EBI-10694655;
CC       Q92529; P04626: ERBB2; NbExp=2; IntAct=EBI-79084, EBI-641062;
CC       Q92529; P21860: ERBB3; NbExp=2; IntAct=EBI-79084, EBI-720706;
CC       Q92529; Q9C0B1-2: FTO; NbExp=3; IntAct=EBI-79084, EBI-18138793;
CC       Q92529; Q08379: GOLGA2; NbExp=3; IntAct=EBI-79084, EBI-618309;
CC       Q92529; A6NEM1: GOLGA6L9; NbExp=3; IntAct=EBI-79084, EBI-5916454;
CC       Q92529; P10721: KIT; NbExp=3; IntAct=EBI-79084, EBI-1379503;
CC       Q92529; Q15323: KRT31; NbExp=6; IntAct=EBI-79084, EBI-948001;
CC       Q92529; Q14525: KRT33B; NbExp=3; IntAct=EBI-79084, EBI-1049638;
CC       Q92529; O76011: KRT34; NbExp=3; IntAct=EBI-79084, EBI-1047093;
CC       Q92529; Q92764: KRT35; NbExp=3; IntAct=EBI-79084, EBI-1058674;
CC       Q92529; Q6A163: KRT39; NbExp=3; IntAct=EBI-79084, EBI-11958242;
CC       Q92529; Q6A162: KRT40; NbExp=6; IntAct=EBI-79084, EBI-10171697;
CC       Q92529; O43790: KRT86; NbExp=3; IntAct=EBI-79084, EBI-9996498;
CC       Q92529; Q6P1K2: PMF1; NbExp=3; IntAct=EBI-79084, EBI-713832;
CC       Q92529; Q8ND90: PNMA1; NbExp=3; IntAct=EBI-79084, EBI-302345;
CC       Q92529; Q96T49: PPP1R16B; NbExp=3; IntAct=EBI-79084, EBI-10293968;
CC       Q92529; P31321: PRKAR1B; NbExp=3; IntAct=EBI-79084, EBI-2805516;
CC       Q92529; P48556: PSMD8; NbExp=3; IntAct=EBI-79084, EBI-359304;
CC       Q92529; Q04864-2: REL; NbExp=3; IntAct=EBI-79084, EBI-10829018;
CC       Q92529; Q9H7B4: SMYD3; NbExp=3; IntAct=EBI-79084, EBI-347919;
CC       Q92529; O75558: STX11; NbExp=3; IntAct=EBI-79084, EBI-714135;
CC       Q92529; Q13077: TRAF1; NbExp=3; IntAct=EBI-79084, EBI-359224;
CC       Q92529; Q12933: TRAF2; NbExp=3; IntAct=EBI-79084, EBI-355744;
CC       Q92529; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-79084, EBI-17716262;
CC       Q92529; Q9BYV2: TRIM54; NbExp=3; IntAct=EBI-79084, EBI-2130429;
CC       Q92529; Q86WV8: TSC1; NbExp=5; IntAct=EBI-79084, EBI-12806590;
CC       Q92529; Q5T6F2: UBAP2; NbExp=3; IntAct=EBI-79084, EBI-2514383;
CC       Q92529; Q8N6Y0: USHBP1; NbExp=3; IntAct=EBI-79084, EBI-739895;
CC       Q92529; Q70EL1-9: USP54; NbExp=3; IntAct=EBI-79084, EBI-11975223;
CC       Q92529; Q9UK41-2: VPS28; NbExp=3; IntAct=EBI-79084, EBI-12146727;
CC       Q92529; Q9NZC7-5: WWOX; NbExp=5; IntAct=EBI-79084, EBI-12040603;
CC       Q92529; P62699: YPEL5; NbExp=3; IntAct=EBI-79084, EBI-11721624;
CC       Q92529; Q9H0C1: ZMYND12; NbExp=3; IntAct=EBI-79084, EBI-12030590;
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=p64;
CC         IsoId=Q92529-1; Sequence=Displayed;
CC       Name=p52;
CC         IsoId=Q92529-2; Sequence=VSP_009805;
CC   -!- TISSUE SPECIFICITY: Mainly expressed in brain. Hardly detectable in
CC       other tissues, except in pancreas. Highly expressed in the cerebral
CC       cortex, frontal and temporal lobes, occipital pole, hippocampus,
CC       caudate nucleus and amygdala. Expressed at low level in the cerebellum,
CC       medulla and spinal cord. {ECO:0000269|PubMed:8808684}.
CC   -!- PTM: Tyrosine phosphorylated. {ECO:0000269|PubMed:12006576}.
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DR   EMBL; D84361; BAA12322.1; -; mRNA.
DR   EMBL; D84361; BAA12323.1; -; mRNA.
DR   EMBL; AL160054; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL353150; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC026314; AAH26314.1; -; mRNA.
DR   CCDS; CCDS6681.1; -. [Q92529-1]
DR   RefSeq; NP_058544.3; NM_016848.5. [Q92529-1]
DR   AlphaFoldDB; Q92529; -.
DR   SMR; Q92529; -.
DR   BioGRID; 119752; 63.
DR   CORUM; Q92529; -.
DR   IntAct; Q92529; 50.
DR   MINT; Q92529; -.
DR   STRING; 9606.ENSP00000364995; -.
DR   GlyGen; Q92529; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q92529; -.
DR   PhosphoSitePlus; Q92529; -.
DR   BioMuta; SHC3; -.
DR   DMDM; 48474922; -.
DR   jPOST; Q92529; -.
DR   MassIVE; Q92529; -.
DR   MaxQB; Q92529; -.
DR   PaxDb; 9606-ENSP00000364995; -.
DR   PeptideAtlas; Q92529; -.
DR   ProteomicsDB; 75289; -. [Q92529-1]
DR   ProteomicsDB; 75290; -. [Q92529-2]
DR   Antibodypedia; 27964; 250 antibodies from 29 providers.
DR   DNASU; 53358; -.
DR   Ensembl; ENST00000375835.9; ENSP00000364995.4; ENSG00000148082.10. [Q92529-1]
DR   GeneID; 53358; -.
DR   KEGG; hsa:53358; -.
DR   MANE-Select; ENST00000375835.9; ENSP00000364995.4; NM_016848.6; NP_058544.3.
DR   UCSC; uc004aqf.2; human. [Q92529-1]
DR   AGR; HGNC:18181; -.
DR   CTD; 53358; -.
DR   DisGeNET; 53358; -.
DR   GeneCards; SHC3; -.
DR   HGNC; HGNC:18181; SHC3.
DR   HPA; ENSG00000148082; Tissue enriched (brain).
DR   MIM; 605263; gene.
DR   neXtProt; NX_Q92529; -.
DR   OpenTargets; ENSG00000148082; -.
DR   PharmGKB; PA134913435; -.
DR   VEuPathDB; HostDB:ENSG00000148082; -.
DR   eggNOG; KOG3697; Eukaryota.
DR   GeneTree; ENSGT00950000182870; -.
DR   HOGENOM; CLU_029532_2_1_1; -.
DR   InParanoid; Q92529; -.
DR   OMA; NTQRIPQ; -.
DR   OrthoDB; 2903566at2759; -.
DR   PhylomeDB; Q92529; -.
DR   TreeFam; TF315807; -.
DR   PathwayCommons; Q92529; -.
DR   Reactome; R-HSA-167044; Signalling to RAS.
DR   Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR   Reactome; R-HSA-8853659; RET signaling.
DR   SignaLink; Q92529; -.
DR   SIGNOR; Q92529; -.
DR   BioGRID-ORCS; 53358; 15 hits in 1151 CRISPR screens.
DR   ChiTaRS; SHC3; human.
DR   GeneWiki; SHC3; -.
DR   GenomeRNAi; 53358; -.
DR   Pharos; Q92529; Tbio.
DR   PRO; PR:Q92529; -.
DR   Proteomes; UP000005640; Chromosome 9.
DR   RNAct; Q92529; Protein.
DR   Bgee; ENSG00000148082; Expressed in Brodmann (1909) area 23 and 157 other cell types or tissues.
DR   ExpressionAtlas; Q92529; baseline and differential.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0001784; F:phosphotyrosine residue binding; IPI:CAFA.
DR   GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
DR   GO; GO:0007417; P:central nervous system development; TAS:ProtInc.
DR   GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:ProtInc.
DR   GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
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; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1.
DR   Gene3D; 3.30.505.10; SH2 domain; 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; IPR035676; SHC_SH2.
DR   PANTHER; PTHR10337; SHC TRANSFORMING PROTEIN; 1.
DR   PANTHER; PTHR10337:SF4; SHC-TRANSFORMING PROTEIN 3; 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; SSF50729; PH domain-like; 1.
DR   SUPFAM; SSF55550; SH2 domain; 1.
DR   PROSITE; PS01179; PID; 1.
DR   PROSITE; PS50001; SH2; 1.
DR   Genevisible; Q92529; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Phosphoprotein; Reference proteome; SH2 domain.
FT   CHAIN           1..594
FT                   /note="SHC-transforming protein 3"
FT                   /id="PRO_0000097734"
FT   DOMAIN          149..334
FT                   /note="PID"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT   DOMAIN          499..590
FT                   /note="SH2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT   REGION          98..147
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          335..498
FT                   /note="CH1"
FT   REGION          351..373
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          386..405
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         402
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61120"
FT   VAR_SEQ         1..155
FT                   /note="MLPRTKYNRFRNDSVTSVDDLLHSLSVSGGGGKVSAARATPAAAPYLVSGEA
FT                   LRKAPDDGPGSLGHLLHKVSHLKLSSSGLRGLSSAARERAGARLSGSCSAPSLAAPDGS
FT                   APSAPRAPAMSAARKGRPGDEPLPRPPRGAPHASDQVLGPGVTY -> MHARAAASVMD
FT                   ICRIRLLIRLTIGLERPPGQV (in isoform p52)"
FT                   /evidence="ECO:0000303|PubMed:8760305,
FT                   ECO:0000303|PubMed:8808684"
FT                   /id="VSP_009805"
FT   CONFLICT        58
FT                   /note="D -> V (in Ref. 4; AAH26314)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        201
FT                   /note="K -> R (in Ref. 2)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        271
FT                   /note="A -> T (in Ref. 4; AAH26314)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        553
FT                   /note="I -> E (in Ref. 2)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        554
FT                   /note="R -> Q (in Ref. 4; AAH26314)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        593..594
FT                   /note="KQ -> NE (in Ref. 2)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   594 AA;  64056 MW;  047A9D08002E41BF CRC64;
     MLPRTKYNRF RNDSVTSVDD LLHSLSVSGG GGKVSAARAT PAAAPYLVSG EALRKAPDDG
     PGSLGHLLHK VSHLKLSSSG LRGLSSAARE RAGARLSGSC SAPSLAAPDG SAPSAPRAPA
     MSAARKGRPG DEPLPRPPRG APHASDQVLG PGVTYVVKYL GCIEVLRSMR SLDFSTRTQI
     TREAISRVCE AVPGAKGAFK KRKPPSKMLS SILGKSNLQF AGMSISLTIS TASLNLRTPD
     SKQIIANHHM RSISFASGGD PDTTDYVAYV AKDPVNRRAC HILECCDGLA QDVIGSIGQA
     FELRFKQYLQ CPTKIPALHD RMQSLDEPWT EEEGDGSDHP YYNSIPSKMP PPGGFLDTRL
     KPRPHAPDTA QFAGKEQTYY QGRHLGDTFG EDWQQTPLRQ GSSDIYSTPE GKLHVAPTGE
     APTYVNTQQI PPQAWPAAVS SAESSPRKDL FDMKPFEDAL KNQPLGPVLS KAASVECISP
     VSPRAPDAKM LEELQAETWY QGEMSRKEAE GLLEKDGDFL VRKSTTNPGS FVLTGMHNGQ
     AKHLLLVDPE GTIRTKDRVF DSISHLINHH LESSLPIVSA GSELCLQQPV ERKQ
//