Q62985 (SH2B1_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified April 3, 2013. Version 83. History...
Names and origin
|Protein names||Recommended name:|
SH2B adapter protein 1
FceRI gamma-chain-interacting protein SH2-B
SH2 domain-containing protein 1B
SH2-B PH domain-containing signaling mediator 1
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||756 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
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
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
Belongs to the SH2B adapter family.
Contains 1 PH domain.
Contains 1 SH2 domain.
|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 key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 756||756||SH2B adapter protein 1||PRO_0000323611|
|Domain||247 – 376||130||PH|
|Domain||527 – 625||99||SH2|
|Region||1 – 555||555||Interaction with JAK2 (low-affinity binding; independent of JAK2 phosphorylation)|
|Region||24 – 85||62||Required for self-association By similarity|
|Region||85 – 196||112||Interaction with RAC1|
|Region||100 – 243||144||Required for NGF signaling|
|Region||224 – 233||10||Required for nuclear localization|
Amino acid modifications
|Modified residue||88||1||Phosphoserine By similarity|
|Modified residue||96||1||Phosphoserine; by MAPK1 or MAPK3; in vitro|
|Modified residue||126||1||Phosphoserine By similarity|
|Modified residue||127||1||Phosphoserine By similarity|
|Modified residue||439||1||Phosphotyrosine; by JAK1, JAK2 and PDGFR Ref.13|
|Modified residue||494||1||Phosphotyrosine; by JAK1, JAK2 Ref.13|
|Modified residue||624||1||Phosphotyrosine By similarity|
|Alternative sequence||632 – 756||125||ERSTS…QYSFV → GREQAGSHAGVCEGDRCYPD ASSTFLPFGASDCVTEHFP in isoform 2.||VSP_032045|
|Mutagenesis||96||1||S → A: Reduces in vitro phosphorylation by MAPK1 and/or MAPK3. Ref.6|
|Mutagenesis||231||1||L → A: Abolishes nuclear localization; when associated with A-233. Ref.14|
|Mutagenesis||233||1||L → A: Abolishes nuclear localization; when associated with A-231. Ref.14|
|Mutagenesis||439||1||Y → F: Fails to enhance GH-induced membrane ruffling; when associated with F-494. Ref.13|
|Mutagenesis||439||1||Y → F: Reduces phosphorylation by JAK1, JAK2 and PDGFRA. Ref.13|
|Mutagenesis||494||1||Y → F: Fails to enhance GH-induced membrane ruffling; when associated with F-439. Ref.13|
|Mutagenesis||494||1||Y → F: Reduces phosphorylation by JAK1 and JAK2. Ref.13|
|Mutagenesis||555||1||R → E: Reduces interaction with JAK2 and abolishes JAK2 kinase activity; reduces GH-stimulated cell motility; abolishes interaction with PDGFRA. Ref.7 Ref.8|
|Sequence conflict||211||1||R → K in AAC04575. Ref.2|
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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, MUTAGENESIS OF SER-96.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|U57391 mRNA. Translation: AAC52601.1.|
AF047577 mRNA. Translation: AAC04575.1.
|RefSeq||NP_001041645.1. NM_001048180.1. |
3D structure databases
|HSSP||HSSP built from PDB template 1RQQ based on UniProtKB Q9Z200. |
|SMR||Q62985. Positions 247-381, 520-627. |
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000074274; ENSRNOP00000066048; ENSRNOG00000049181. |
|RGD||620132. Sh2b1. |
Gene expression databases
Family and domain databases
|Gene3D||188.8.131.52. 1 hit. |
3.30.505.10. 1 hit.
|InterPro||IPR011993. PH_like_dom. |
|Pfam||PF00169. PH. 1 hit. |
PF08916. Phe_ZIP. 1 hit.
PF00017. SH2. 1 hit.
|PRINTS||PR00401. SH2DOMAIN. |
|SMART||SM00233. PH. 1 hit. |
SM00252. SH2. 1 hit.
|SUPFAM||SSF109805. Phe_ZIP. 1 hit. |
|PROSITE||PS50003. PH_DOMAIN. False negative. |
PS50001. SH2. 1 hit.
|Accession||Primary (citable) accession number: Q62985|
Secondary accession number(s): O55072
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families