EGF or PDGF receptors activate atypical PKClambda through phosphatidylinositol 3-kinase.

Abstract

Overexpression of a TPA‐insensitive PKC member, an atypical protein kinase C (aPKClambda), 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 aPKClambda from the nucleus to the cytosol, indicating the activation of aPKClambda in response to this growth factor stimulation. These immediate signal‐dependent changes in aKPClambda 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, p110alpha, inhibited aPKClambda‐dependent activation of TRE in Y40/51 cells stimulated with PDGF. Overexpression of p110alpha resulted in an enhancement of TRE expression in response to PDGF and the regulatory domain of aPKClambda 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 aPKClambda through PI3‐kinase.

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

“…Host cell proliferation can be blocked by pharmacological inhibition of PI3-K In many different systems, PI3-K activity has been linked to proliferative pathways via activation of MAP kinase (Karnitz et al, 1995), p70S6K (Alessi et al, 1997), c-Jun N-terminal kinase (JNK) (Klippel et al, 1996), PKB or proteins of the PKC family (Akimoto et al, 1996;Sontag et al, 1997). To examine whether the continuous proliferation of T. parva-infected B cells depends on PI3-K activity, we took advantage of two unrelated PI3-K inhibitors, LY294002 and wortmannin.…”

“…In concert with PKB, PDK1 was shown to activate p70S6 kinase (Alessi et al, 1997), an enzyme critical for cell cycle progression through G1-and S-phase entry (Lane et al, 1993;Reinhard et al, 1994). Other downstream effector kinases of PI3-K are the atypical PKCz (Chou et al, 1998) and PKCl (Akimoto et al, 1996; and protein tyrosine kinases of the Tec family, such as Btk (Scharenberg et al, 1998).…”

Regulation of glioblastoma cell invasion by PKCι and RhoB

“…Both of these mutations have been linked to increased motility and invasion because of their aberrant activation of the phosphoinositide 3-kinase (PI3K) pathway (Tamura et al, 1999;Cai et al, 2005). The PI3K pathway activates multiple downstream kinases including protein kinase C type i (PKCi), a member of the atypical protein kinase C family (Akimoto et al, 1996). PKCi activation involves phosphorylation by PDK1 and binding to a Cdc42 family protein (Kanzaki et al, 2004).…”

Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress

“…Calcium and DAG are required to activate cPKCs, whereas calcium is not required for nPKC activation. aPKCs do not require these factors when activated by certain lipid species, such as the products of phosphatidylinositol (PI) 3-kinase and ceramide (1,16,38,50). A growing body of evidence indicates that cPKCs and nPKCs play divergent roles in controlling cell growth, differentiation, apoptosis, and carcinogenesis (40).…”