SH2B adapter protein 1; SH2 domain-containing protein 1B; Pro-rich, PH & SH2 domain-containing signaling mediator (PSM, SH2B1, KIAA1299, SH2B)
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Function
- adapter protein for several members of the tyrosine kinase receptor family
- involved in multiple signaling pathways mediated by Janus kinase (JAK) & receptor tyrosine kinases, including the receptors of: insulin, insulin-like growth factor-1 (IGF1) nerve growth factor (NGF) brain-derived neurotrophic factor (BDNF) glial cell line-derived neurotrophic factor (GDNF) platelet-derived growth factor (PDGF) fibroblast growth factors (FGFs)
- in growth hormone signaling, autophosphorylated Tyr-813 JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on Tyr
- these phosphorylated-Tyr form potential binding sites for other signaling proteins
- growth hormone also promotes Ser/Thr phosphorylation of SH2B1 & these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1
- in leptin signaling, binds to & potentiates the activation of JAK2 by globally enhancing downstream pathways
- in response to leptin, binds simultaneously to both, JAK2 & IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 & IRS1 or IRS2
- mediates tyrosine phosphorylation of IRS1 & 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 & AKT1 enzymatic activity
- enhances the kinase activity of the cytokine receptor- associated tyrosine kinase JAK2 & of other receptor tyrosine kinases, such as FGFR3 & NTRK1
- for JAK2, the mechanism seems to involve dimerization of both, SH2B1 & JAK2
- enhances RET phosphorylation & kinase activity
- isoforms seem to be differentially involved in IGF1 & PDGF-induced mitogenesis self-associates
- forms a heteromultimeric complex with SH2B2 (putative)
- interacts with SH2B2
- isoform 1 interacts via its SH2 domain with JAK2
- isoform 2 interacts via its SH2 domain & its N-terminus with JAK2
- SH2 domain is required for the major interaction with JAK2 phosphorylated on Tyr
- the N-terminus provides a low-affinity binding to JAK2 independent of JAK2 phosphorylation
- isoform 3 interacts via its SH2 domain with JAK2
- isoform 1 interacts via its SH2 domain with INSR, interaction requires receptor activation
- isoform 3 interacts via its SH2 domain with INSR, the interaction requires receptor activation & requires INSR phosphorylation at Tyr-1185
- isoform 1 interacts with IGF1R; the interaction requires receptor activation
- isoform 2 interacts with PRKAR1A/RET (PTC2) fusion protein, the interaction requires RET Tyr-905 & Tyr-981
- isoform 2 interacts via its SH2 domain with FGFR3, the interaction requires FGFR3 Tyr-724 & Tyr-760
- isoform 2 interacts with RET, the interaction requires RET kinase activity & RET Tyr-981
- isoform 2 interacts with RAC1
- isoform 2 interacts with PDGFRA &/or PDGFRB; interaction requires receptor activation
- interacts with ISR1 & ISR2
- isoform 3 is probably part of a complex consisting of INSR, ISR1 & SH2B1
- probably part of a ternary complex consisting of SH2B1, JAK2 & ISR1 or ISR2
- may interact with FCER1G (putative)
- phosphorylated on Tyr in response to receptor kinase stimulation
- phosphorylated by RET
Structure
- homopentamer (putative).
- belongs to the SH2B adapter family
- contains 1 PH domain
- contains 1 SH2 domain
Compartment
Alternative splicing
named isoforms=3
Expression
- widely expressed with highest levels in skeletal muscle & ovary