Regulation of Phosphoinositide 3-Kinase by Its Intrinsic Serine Kinase Activity In Vivo
AUTOR(ES)
Foukas, Lazaros C.
FONTE
American Society for Microbiology
RESUMO
One potentially important mechanism for regulating class Ia phosphoinositide 3-kinase (PI 3-kinase) activity is autophosphorylation of the p85α adapter subunit on Ser608 by the intrinsic protein kinase activity of the p110 catalytic subunit, as this downregulates the lipid kinase activity in vitro. Here we investigate whether this phosphorylation can occur in vivo. We find that p110α phosphorylates p85α Ser608 in vivo with significant stoichiometry. However, p110β is far less efficient at phosphorylating p85α Ser608, identifying a potential difference in the mechanisms by which these two isoforms are regulated. The p85α Ser608 phosphorylation was increased by treatment with insulin, platelet-derived growth factor, and the phosphatase inhibitor okadaic acid. The functional effects of this phosphorylation are highlighted by mutation of Ser608, which results in reduced lipid kinase activity and reduced association of the p110α catalytic subunit with p85α. The importance of this phosphorylation was further highlighted by the finding that autophosphorylation on Ser608 was impaired, while lipid kinase activity was increased, in a p85α mutant recently discovered in human tumors. These results provide the first evidence that phosphorylation of Ser608 plays a role as a shutoff switch in growth factor signaling and contributes to the differences in functional properties of different PI 3-kinase isoforms in vivo.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=321424Documentos Relacionados
- A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity.
- PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity.
- Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation.
- Caveolin 1-Mediated Regulation of Receptor Tyrosine Kinase-Associated Phosphatidylinositol 3-Kinase Activity by Ceramide
- p110δ, a novel phosphoinositide 3-kinase in leukocytes
