Biochemical Society Transactions

673rd Meeting

Functional effects of APS and SH2-B on insulin receptor signalling

Z. Ahmed, T. S. Pillay

Abstract

APS [for ‘adapter protein with a pleckstrin homology (PH) and Src homology 2 (SH2) domain’] belongs to a family of adapter proteins involved in signalling by the receptors for insulin, insulin-like growth factor 1, platelet-derived growth factor and nerve growth factor. Other members include alternatively spliced SH2-B isoforms (SH2Bα. SH2-Byβ and SH2-Bγ) and Lnk. These have a C-terminal SH2 domain, a central PH domain and an N-terminal proline-rich region. SH2Bα, APS and Lnk have a conserved C-terminal tyrosine phosphorylation site, whereas the alternatively spliced SH2-Bβ and SH2-Bγ have distinct C-termini. There is considerable sequence similarity between APS, SH2-B and Lnk, particularly in the SH2 domain. Both APS and SH2-Bα interact with the insulin-receptor activation loop phosphorylation sites and undergo insulin-stimulated tyrosine phosphorylation, although the phosphorylation of SH2-B is considerably weaker. APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor. We established cell lines [Chinese hamster ovary (CHO). T-APS and CHO. T-SH2-B cells] overexpressing APS and SH2-Bα to study their roles in insulin receptor signalling. Either adapter protein enhances insulin receptor and ERK (extracellular-signal-regulated kinase) phosphorylation. In CHO. T-APS cells, Akt phosphorylation is observed earlier than in CHO.T-SH2-B cells. Both enhance insulin-stimulated Akt activation but APS seems to cause greater activation. Thus APS and SH2-B have similar effects on insulin receptor signalling, although the effects of SH2-B are independent of its phosphorylation.

  • adapter protein
  • insulin
  • insulin receptor phosphorylation
  • SH2 domain
  • APS, adapter protein with a PH and SH2 domain
  • BCR, B-cell antigen receptor
  • CAP, c-Cbl-associated protein
  • CHO, Chinese hamster ovary
  • EGF, epidermal growth factor
  • ERK, extracellular-signal-regulated kinase
  • IGF, insulin-like growth factor
  • IRS, insulin receptor substrate(s)
  • ITAM, immuno-receptor tyrosine-binding activation motif
  • JAK, Janus kinase
  • PDGF, platelet-derived growth factor
  • PH, pleckstrin homology
  • SH2, Src homology 2