Q6S5L8 (SHC4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
SHC-transforming protein 4

Alternative name(s):
Rai-like protein
Short name=RaLP
SHC-transforming protein D
Short name=hShcD
Src homology 2 domain-containing-transforming protein C4
Short name=SH2 domain protein C4

Gene names

Name:	SHC4
Synonyms:	SHCD
ORF Names:	UNQ6438/PRO21364

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	630 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Activates both Ras-dependent and Ras-independent migratory pathways in melanomas. Contributes to the early phases of agrin-induced tyrosine phosphorylation of CHRNB1. Ref.1
Subunit structure	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. Ref.4
Subcellular location	Cell junction › synapse › postsynaptic cell membrane. Note: Colocalized with MUSK at the neuromuscular junction By similarity.
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. Ref.1
Post-translational modification	Phosphorylated; the phosphorylation is enhanced by EGF. Phosphorylation at Tyr-424 is required for the interaction with GRB2. Ref.4
Sequence similarities	Contains 1 PID domain. Contains 1 SH2 domain.

Ontologies

Keywords
Cellular component	Cell junction Cell membrane Membrane Postsynaptic cell membrane Synapse
Coding sequence diversity	Alternative splicing Polymorphism
Domain	SH2 domain
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	intracellular signal transduction Inferred from electronic annotation. Source: InterPro
Cellular_component	cell junction Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW postsynaptic membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q6S5L8-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q6S5L8-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-243: Missing.
     244-280: KFLSTVLGKSNLQFSGMNIKLTISTCSLTLMNLDNQQ → MLPALEHWIPKFFSFRTRTGSPLSLACRQPIVGPCDH

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 630	630	SHC-transforming protein 4		PRO_0000337200
Regions
	Domain	186 – 369	184	PID
	Domain	526 – 617	92	SH2
	Region	1 – 185	185	CH2
	Region	370 – 525	156	CH1
Amino acid modifications
	Modified residue	424	1	Phosphotyrosine
Natural variations
	Alternative sequence	1 – 243	243	Missing in isoform 2.		VSP_033965
	Alternative sequence	244 – 280	37	KFLST…LDNQQ → MLPALEHWIPKFFSFRTRTG SPLSLACRQPIVGPCDH in isoform 2.		VSP_033966
	Natural variant	52	1	N → D. Ref.3 Corresponds to variant rs17856991 [ dbSNP | Ensembl ].		VAR_043672
	Natural variant	244	1	K → E. Ref.3 Corresponds to variant rs17856990 [ dbSNP | Ensembl ].		VAR_043673
	Natural variant	400	1	Q → H. Corresponds to variant rs16961728 [ dbSNP | Ensembl ].		VAR_043674
	Natural variant	447	1	D → G. Ref.3 Corresponds to variant rs17856992 [ dbSNP | Ensembl ].		VAR_043675
Experimental info
	Mutagenesis	315	1	R → Q: Phosphorylation is markedly decreased. Completely reduces the phosphorylation and interaction with MUSK; when associated with K-549. Ref.4
	Mutagenesis	374 – 375	2	YY → F: Remains phosphorylated. Contains a residual phosphorylation; when associated with F-465. Retains the ability to bind MUSK. Reduced the phosphorylation in presence of MUSK; when associated with F-424 and F-465. Completely abolishes the phosphorylation in presence of MUSK; when associated with F-403; F-413; F-424 and F-465. Retains the ability to bind MUSK; when associated with F-465. Retains the ability to bind MUSK; when associated with F-424 and F-465. Retains the ability to bind MUSK; when associated with F-403; F-413; F-424 and F-465. Ref.4
	Mutagenesis	403	1	Y → F: Completely abolishes the phosphorylation in presence of MUSK; when associated with 374-F-F-375; F-413; F-424 and F-465. Ref.4
	Mutagenesis	413	1	Y → F: Completely abolishes the phosphorylation in presence of MUSK; when associated with 374-F-F-375; F-403; F-424 and F-465. Ref.4
	Mutagenesis	424	1	Y → F: Significantly decreased GRB2 interaction. Reduced the phosphorylation in presence of MUSK; when associated with 374-F-F-375 and F-465. Completely abolishes the phosphorylation in presence of MUSK; when associated with 374-F-F-375; F-403; F-413 and F-465. Ref.4
	Mutagenesis	465	1	Y → F: Remains phosphorylated. Contains a residual phosphorylation; when associated with 374-F-F-375. Reduced the phosphorylation in presence of MUSK; when associated with 374-F-F-375 and 424. Completely abolishes the phosphorylation in presence of MUSK; when associated with 374-F-F-375; F-403; F-413 and F-424. Retains the ability to bind MUSK. Retains the ability to bind MUSK; when associated with 374-F-F-375. Retains the ability to bind MUSK; when associated with 374-F-F-375 and F-424. Retains the ability to bind MUSK; when associated with 374-F-F-375; F-403; F-413 and F-424. Ref.4
	Mutagenesis	549	1	R → K: Completely reduces the phosphorylation and interaction with MUSK; when associated with Q-315. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 5, 2004. Version 1. Checksum: 504F3FCB894E2C59	FASTA	630	68,785
	10 20 30 40 50 60 MRERGQDSLA GLVLYVGLFG HPGMLHRAKY SRFRNESITS LDEGSSGGSV GNKGSPQPPH 70 80 90 100 110 120 PALAPHLPTE DATLPSQESP TPLCTLIPRM ASMKLANPAT LLSLKNFCLG TKEVPRLKLQ 130 140 150 160 170 180 ESRDPGSSGP SSPETSLSRS GTAPPPQQDL VGHRATALTP DSCPLPGPGE PTLRSRQDRH 190 200 210 220 230 240 FLQHLLGMGM NYCVRYMGCV EVLQSMRSLD FGMRTQVTRE AISRLCEAVP GANGAIKKRK 250 260 270 280 290 300 PPVKFLSTVL GKSNLQFSGM NIKLTISTCS LTLMNLDNQQ IIANHHMQSI SFASGGDPDT 310 320 330 340 350 360 TDYVAYVAKD PVNQRACHIL ECHNGMAQDV ISTIGQAFEL RFKQYLKNPS LNTSCESEEV 370 380 390 400 410 420 HIDSHAEERE DHEYYNEIPG KQPPVGGVSD MRIKVQATEQ MAYCPIQCEK LCYLPGNSKC 430 440 450 460 470 480 SSVYENCLEQ SRAIGNVHPR GVQSQRDTSL LKHTCRVDLF DDPCYINTQA LQSTPGSAGN 490 500 510 520 530 540 QRSAQPLGSP WHCGKAPETV QPGATAQPAS SHSLPHIKQQ LWSEECYHGK LSRKAAESLL 550 560 570 580 590 600 VKDGDFLVRE SATSPGQYVL SGLQGGQAKH LLLVDPEGKV RTKDHVFDNV GHLIRYHMDN 610 620 630 SLPIISSGSE VSLKQPVRKD NNPALLHSNK
	Isoform 2 [UniParc]. Checksum: 558D4E2167B69AF7	FASTA	387	42,782
	10 20 30 40 50 60 MLPALEHWIP KFFSFRTRTG SPLSLACRQP IVGPCDHIIA NHHMQSISFA SGGDPDTTDY 70 80 90 100 110 120 VAYVAKDPVN QRACHILECH NGMAQDVIST IGQAFELRFK QYLKNPSLNT SCESEEVHID 130 140 150 160 170 180 SHAEEREDHE YYNEIPGKQP PVGGVSDMRI KVQATEQMAY CPIQCEKLCY LPGNSKCSSV 190 200 210 220 230 240 YENCLEQSRA IGNVHPRGVQ SQRDTSLLKH TCRVDLFDDP CYINTQALQS TPGSAGNQRS 250 260 270 280 290 300 AQPLGSPWHC GKAPETVQPG ATAQPASSHS LPHIKQQLWS EECYHGKLSR KAAESLLVKD 310 320 330 340 350 360 GDFLVRESAT SPGQYVLSGL QGGQAKHLLL VDPEGKVRTK DHVFDNVGHL IRYHMDNSLP 370 380 IISSGSEVSL KQPVRKDNNP ALLHSNK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas." Fagiani E., Giardina G., Luzi L., Cesaroni M., Quarto M., Capra M., Germano G., Bono M., Capillo M., Pelicci P., Lanfrancone L. Cancer Res. 67:3064-3073(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY.
[2]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANTS ASP-52; GLU-244 AND GLY-447. Tissue: Testis.
[4]	"Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase." Jones N., Hardy W.R., Friese M.B., Jorgensen C., Smith M.J., Woody N.M., Burden S.J., Pawson T. Mol. Cell. Biol. 27:4759-4773(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MUSK AND GRB2, PHOSPHORYLATION, MUTAGENESIS OF ARG-315; 374-TYR-TYR-375; TYR-403; TYR-413; TYR-424; TYR-465 AND ARG-549.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY464565 mRNA. Translation: AAR19363.1. AY358250 mRNA. Translation: AAQ88617.1. BC033907 mRNA. Translation: AAH33907.1.
IPI	IPI00217895. IPI00747728.
RefSeq	NP_976224.3. NM_203349.3.
UniGene	Hs.642615.
3D structure databases
HSSP	HSSP built from PDB template 1OY2 based on UniProtKB P29353.
ProteinModelPortal	Q6S5L8.
SMR	Q6S5L8. Positions 185-377, 520-619.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000329668.
PTM databases
PhosphoSite	Q6S5L8.
Polymorphism databases
DMDM	74722804.
Proteomic databases
PaxDb	Q6S5L8.
PRIDE	Q6S5L8.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000332408; ENSP00000329668; ENSG00000185634. ENST00000396535; ENSP00000379786; ENSG00000185634.
GeneID	399694.
KEGG	hsa:399694.
UCSC	uc001zxb.1. human. uc010uey.1. human.
Organism-specific databases
CTD	399694.
GeneCards	GC15M049115.
H-InvDB	HIX0202177.
HGNC	HGNC:16743. SHC4.
neXtProt	NX_Q6S5L8.
PharmGKB	PA142670917.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG315087.
HOGENOM	HOG000231974.
HOVERGEN	HBG050121.
InParanoid	Q6S5L8.
KO	K06279.
OMA	ISTCSLT.
OrthoDB	EOG4GF3DQ.
PhylomeDB	Q6S5L8.
Gene expression databases
ArrayExpress	Q6S5L8.
Bgee	Q6S5L8.
CleanEx	HS_SHC4.
Genevestigator	Q6S5L8.
Family and domain databases
Gene3D	2.30.29.30. 1 hit. 3.30.505.10. 1 hit.
InterPro	IPR011993. PH_like_dom. IPR006019. PID_domain. IPR006020. PTyr_interaction_dom. IPR000980. SH2. [Graphical view]
Pfam	PF00640. PID. 1 hit. PF00017. SH2. 1 hit. [Graphical view]
PRINTS	PR00401. SH2DOMAIN. PR00629. SHCPIDOMAIN.
SMART	SM00462. PTB. 1 hit. SM00252. SH2. 1 hit. [Graphical view]
PROSITE	PS01179. PID. 1 hit. PS50001. SH2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	SHC4. human.
GenomeRNAi	399694.
NextBio	105503.

Entry information

Entry name

SHC4_HUMAN

Accession

Primary (citable) accession number: Q6S5L8
Secondary accession number(s): Q6UXQ3, Q8IYW3

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 20, 2008
Last sequence update:	July 5, 2004
Last modified:	May 1, 2013
This is version 81 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.