EGF or PDGF receptors activate atypical PKCλ, through phosphatidylinositol 3-kinase

Abstract

Overexpression of a TPA-insensitive PKC member, an atypical protein kinase C (aPKCλ), results in an enhancement of the transcriptional activation of TPA response element (TRE) in cells stimulated with epidermal growth factor (EGF) or platelet-derived growth factor (PDGF). EGF or PDGF also caused a transient increase in the in vivo phosphorylation level and a change in the intracellular localization of aPKCλ from the nucleus to the cytosol, indicating the activation of aPKCλ in response to this growth factor stimulation. These immediate signal-dependent changes in aPKCλ were observed for a PDGF receptor add-back mutant (Y40/51) that possesses only two of the five major autophosphorylation sites and binds PI3-kinase, and were inhibited by wortmannin, an inhibitor of PI3-kinase. Furthermore, an N-terminal fragment of the catalytic subunit of PI3-kinase, p110α, inhibited aPKCλ-dependent activation of TRE in Y40/51 cells stimulated with PDGF. Overexpression of p110α resulted in an enhancement of TRE expression in response to PDGF and the regulatory domain of aPKCλ inhibited this TRE activation in Y40/51 cells. These results provide the first in vivo evidence supporting the presence of a novel signalling pathway from receptor tyrosine kinases to aPKCλ through PI3-kinase.