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Q62985 (SH2B1_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 93. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
SH2B adapter protein 1
Alternative name(s):
FceRI gamma-chain-interacting protein SH2-B
SH2 domain-containing protein 1B
SH2-B PH domain-containing signaling mediator 1
Gene names
Name:Sh2b1
Synonyms:Sh2-b, Sh2bpsm1
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length756 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis By similarity. Ref.2 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.11 Ref.15

Subunit structure

Self-associates. Homopentamer. Forms a heteromultimeric complex with SH2B2. Interacts with SH2B2. Isoform 1 interacts via its SH2 domain with JAK2. Isoform 2 interacts via its SH2 domain and its N-terminus with JAK2; the SH2 domain is required for the major interaction with JAK2 phosphorylated on tyrosine residues; the N-terminus provides a low-affinity binding to JAK2 independent of JAK2 phosphorylation. Isoform 1 interacts via its SH2 domain with INSR; the interaction requires receptor activation. Isoform 1 interacts with IGF1R; the interaction requires receptor activation. Isoform 2 interacts via its SH2 domain with FGFR3. Isoform 2 interacts with RET; the interaction requires RET kinase activity. Isoform 2 interacts with RAC1. Isoform 2 interacts with PDGFRA and/or PDGFRB; the interaction requires receptor activation. Interacts with ISR1 and ISR2. Probably part of a complex consisting of INSR, ISR1 and SH2B1. Probably part of a ternary complex consisting of SH2B1, JAK2 and ISR1 or ISR2 By similarity. May interact with FCER1G. Interacts (via SH2 domain) with NTRK1 (phosphorylated). Ref.1 Ref.2 Ref.4 Ref.5 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.15

Subcellular location

Cytoplasm. Membrane Probable. Nucleus. Note: Shuttles between the nucleus and the cytoplasm. Ref.14

Tissue specificity

Isoform 1 is ubiquitously expressed. Expressed in epididymal adipose tissue, liver and skeletal muscle. Ref.3

Post-translational modification

Phosphorylated on tyrosine residues in response to treatment with growth hormone (GH), IFN-gamma (IFNG), BDNF, PDGF and FGF. Phosphorylated on tyrosine residues by JAK2 and JAK1. Phosphorylated on multiple serine and threonine residues in response to treatment with NGF. Phosphorylated on serine residues. Ref.2 Ref.5 Ref.6 Ref.10 Ref.13

Sequence similarities

Belongs to the SH2B adapter family.

Contains 1 PH domain.

Contains 1 SH2 domain.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

RETP079493EBI-7395583,EBI-2480756From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q62985-1)

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: Q62985-2)

The sequence of this isoform differs from the canonical sequence as follows:
     632-756: ERSTSRDPTQ...RAINNQYSFV → GREQAGSHAG...ASDCVTEHFP

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 756756SH2B adapter protein 1
PRO_0000323611

Regions

Domain247 – 376130PH
Domain527 – 62599SH2
Region1 – 555555Interaction with JAK2 (low-affinity binding; independent of JAK2 phosphorylation)
Region24 – 8562Required for self-association By similarity
Region85 – 196112Interaction with RAC1
Region100 – 243144Required for NGF signaling
Region224 – 23310Required for nuclear localization

Amino acid modifications

Modified residue881Phosphoserine By similarity
Modified residue961Phosphoserine; by MAPK1 or MAPK3; in vitro Ref.6
Modified residue4391Phosphotyrosine; by JAK1, JAK2 and PDGFR Ref.13
Modified residue4941Phosphotyrosine; by JAK1, JAK2 Ref.13
Modified residue6241Phosphotyrosine By similarity

Natural variations

Alternative sequence632 – 756125ERSTS…QYSFV → GREQAGSHAGVCEGDRCYPD ASSTFLPFGASDCVTEHFP in isoform 2.
VSP_032045

Experimental info

Mutagenesis961S → A: Reduces in vitro phosphorylation by MAPK1 and/or MAPK3. Ref.6
Mutagenesis2311L → A: Abolishes nuclear localization; when associated with A-233. Ref.14
Mutagenesis2331L → A: Abolishes nuclear localization; when associated with A-231. Ref.14
Mutagenesis4391Y → F: Fails to enhance GH-induced membrane ruffling; when associated with F-494. Ref.13
Mutagenesis4391Y → F: Reduces phosphorylation by JAK1, JAK2 and PDGFRA. Ref.13
Mutagenesis4941Y → F: Fails to enhance GH-induced membrane ruffling; when associated with F-439. Ref.13
Mutagenesis4941Y → F: Reduces phosphorylation by JAK1 and JAK2. Ref.13
Mutagenesis5551R → E: Reduces interaction with JAK2 and abolishes JAK2 kinase activity; reduces GH-stimulated cell motility; abolishes interaction with PDGFRA. Ref.7 Ref.8
Sequence conflict2111R → K in AAC04575. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: D4FCF3086CF3DFE0

FASTA75679,637
        10         20         30         40         50         60 
MNGAPSPEDG VFPSPPALPP PPPPSWQEFC ESHARAAALD LARRFRLYLA SHPQYAEPGA 

        70         80         90        100        110        120 
EAAFSGRFAE LFLQHFEAEV ARASGSLSPP VLAPLSPGVE IPPSHDLSLE SCRVGGPLAV 

       130        140        150        160        170        180 
LGPSRSSEDL AGPLPSSVSS STTSSKPKLK KRFSLRSVGR SVRGSVRGIL QWRGAVESPS 

       190        200        210        220        230        240 
QAGPLETTSG PPVLGGNSNS NSSGGAGTVG RALANDGTSP GERWTHRFER LRLSRGGGTL 

       250        260        270        280        290        300 
RDGAGVIQRE ELLSFMGAEE AAPDPAGVGR GGGAAGLTSG GGGQPQWQKC RLLLRSEGEG 

       310        320        330        340        350        360 
GGGSRLEFFV PPKASRPRLS IPCSTITDVR TATALEMPDR ENTFVVKVEG PSEYILETTD 

       370        380        390        400        410        420 
ALHVKAWVSD IQECLSPGPC PAISPRPMTL PLAPGTSFLT KDNTESLELP CLNHSESLPS 

       430        440        450        460        470        480 
QDLLLGPSES NDRLSQGAYG GLSDRPSASF SPSSASIAAS HFDSMELLPP ELPPRIPIEE 

       490        500        510        520        530        540 
GPPAGTVHPL STPYPPLDTP EAATGSFLFQ GEAEGGEGDQ PLSGYPWFHG MLSRLKAAQL 

       550        560        570        580        590        600 
VLEGGTSSHG VFLVRQSETR RGEYVLTFNF QGKAKHLRLS LNEEGQCRVQ HLWFQSIFDM 

       610        620        630        640        650        660 
LEHFRVHPIP LESGGSSDVV LVSYVPSQRQ QERSTSRDPT QPSEPPPWTD PPHPGAEEAS 

       670        680        690        700        710        720 
GAPEVAAATA AAAKERQEKE KAGGGGVQEE LVPMAELVPM AELEEAIAPG TEAQGGAGSS 

       730        740        750 
GDLEVSLMVQ LQQLPLGGNG EEGGHPRAIN NQYSFV 

« Hide

Isoform 2 [UniParc].

Checksum: 868D9F7591C5E36D
Show »

FASTA67070,931

References

[1]"The yeast tribrid system -- genetic detection of trans-phosphorylated ITAM-SH2-interactions."
Osborne M.A., Dalton S., Kochan J.P.
Biotechnology (N.Y.) 13:1474-1478(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH FCER1G.
Tissue: Mast cell.
[2]"Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling."
Rui L., Mathews L.S., Hotta K., Gustafson T.A., Carter-Su C.
Mol. Cell. Biol. 17:6633-6644(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, PHOSPHORYLATION, INTERACTION WITH JAK2.
Tissue: Kidney.
[3]"SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase."
Kotani K., Wilden P., Pillay T.S.
Biochem. J. 335:103-109(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[4]"Platelet-derived growth factor (PDGF) stimulates the association of SH2-Bbeta with PDGF receptor and phosphorylation of SH2-Bbeta."
Rui L., Carter-Su C.
J. Biol. Chem. 273:21239-21245(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PDGFRA/B.
[5]"Identification and characterization of novel substrates of Trk receptors in developing neurons."
Qian X., Riccio A., Zhang Y., Ginty D.D.
Neuron 21:1017-1029(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NGF SIGNALING, INTERACTION WITH NTRK1, PHOSPHORYLATION.
[6]"SH2-B, a membrane-associated adapter, is phosphorylated on multiple serines/threonines in response to nerve growth factor by kinases within the MEK/ERK cascade."
Rui L., Herrington J., Carter-Su C.
J. Biol. Chem. 274:26485-26492(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NGF SIGNALING, PHOSPHORYLATION AT SER-96, MUTAGENESIS OF SER-96.
[7]"Identification of SH2-bbeta as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2."
Rui L., Carter-Su C.
Proc. Natl. Acad. Sci. U.S.A. 96:7172-7177(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN JAK2 ACTIVATION, MUTAGENESIS OF ARG-555.
[8]"Differential binding to and regulation of JAK2 by the SH2 domain and N-terminal region of SH2-bbeta."
Rui L., Gunter D.R., Herrington J., Carter-Su C.
Mol. Cell. Biol. 20:3168-3177(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH JAK2, MUTAGENESIS OF ARG-555.
[9]"SH2-B and APS are multimeric adapters that augment TrkA signaling."
Qian X., Ginty D.D.
Mol. Cell. Biol. 21:1613-1620(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBUNIT, INTERACTION WITH SH2B2.
[10]"SH2-B family members differentially regulate JAK family tyrosine kinases."
O'Brien K.B., O'Shea J.J., Carter-Su C.
J. Biol. Chem. 277:8673-8681(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH JAK1; JAK2 AND JAK3, PHOSPHORYLATION.
[11]"SH2-Bbeta is a Rac-binding protein that regulates cell motility."
Diakonova M., Gunter D.R., Herrington J., Carter-Su C.
J. Biol. Chem. 277:10669-10677(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIN REORGANIZATION, INTERACTION WITH RAC1.
[12]"Interaction of fibroblast growth factor receptor 3 and the adapter protein SH2-B. A role in STAT5 activation."
Kong M., Wang C.S., Donoghue D.J.
J. Biol. Chem. 277:15962-15970(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FGFR3.
[13]"YXXL motifs in SH2-Bbeta are phosphorylated by JAK2, JAK1, and platelet-derived growth factor receptor and are required for membrane ruffling."
O'Brien K.B., Argetsinger L.S., Diakonova M., Carter-Su C.
J. Biol. Chem. 278:11970-11978(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-439 AND TYR-494, MUTAGENESIS OF TYR-439 AND TYR-494.
[14]"Adapter protein SH2-B beta undergoes nucleocytoplasmic shuttling: implications for nerve growth factor induction of neuronal differentiation."
Chen L., Carter-Su C.
Mol. Cell. Biol. 24:3633-3647(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF LEU-231 AND LEU-233.
[15]"Interaction of SH2-Bbeta with RET is involved in signaling of GDNF-induced neurite outgrowth."
Zhang Y., Zhu W., Wang Y.G., Liu X.J., Jiao L., Liu X., Zhang Z.H., Lu C.L., He C.
J. Cell Sci. 119:1666-1676(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN GDNF SIGNALING, INTERACTION WITH RET.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U57391 mRNA. Translation: AAC52601.1.
AF047577 mRNA. Translation: AAC04575.1.
RefSeqNP_001041645.1. NM_001048180.1.
NP_604451.2. NM_134456.3. [Q62985-1]
XP_006230415.1. XM_006230353.1. [Q62985-1]
XP_006230416.1. XM_006230354.1. [Q62985-1]
UniGeneRn.11069.

3D structure databases

ProteinModelPortalQ62985.
SMRQ62985. Positions 247-381, 520-627.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid250140. 3 interactions.
IntActQ62985. 2 interactions.
MINTMINT-1528512.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000074274; ENSRNOP00000066048; ENSRNOG00000049181. [Q62985-1]
GeneID89817.
KEGGrno:89817.

Organism-specific databases

CTD25970.
RGD620132. Sh2b1.

Phylogenomic databases

GeneTreeENSGT00530000063355.
HOVERGENHBG006707.
KOK12459.
OMAQEPNTSH.
PhylomeDBQ62985.

Gene expression databases

GenevestigatorQ62985.

Family and domain databases

Gene3D2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProIPR011993. PH_like_dom.
IPR015012. Phe_ZIP.
IPR001849. Pleckstrin_homology.
IPR000980. SH2.
[Graphical view]
PfamPF00169. PH. 1 hit.
PF08916. Phe_ZIP. 1 hit.
PF00017. SH2. 1 hit.
[Graphical view]
PRINTSPR00401. SH2DOMAIN.
SMARTSM00233. PH. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view]
SUPFAMSSF109805. SSF109805. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEPS50001. SH2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio617706.
PROQ62985.

Entry information

Entry nameSH2B1_RAT
AccessionPrimary (citable) accession number: Q62985
Secondary accession number(s): O55072
Entry history
Integrated into UniProtKB/Swiss-Prot: March 18, 2008
Last sequence update: November 1, 1996
Last modified: July 9, 2014
This is version 93 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families