Regulation of protein kinase C ζ by PI 3-kinase and PDK-1

被引:548
作者
Chou, MM
Hou, WM
Johnson, J
Graham, LK
Lee, MH
Chen, CS
Newton, AC
Schaffhausen, BS
Toker, A
机构
[1] Boston Biomed Res Inst, Signal Transduct Grp, Boston, MA 02114 USA
[2] Univ Penn, Sch Med, Dept Dev & Cell Biol, Philadelphia, PA 19104 USA
[3] Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA
[4] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
[5] Univ Kentucky, Coll Pharm, Dept Med Chem & Pharmaceut, Lexington, KY 40536 USA
关键词
D O I
10.1016/S0960-9822(98)70444-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Protein kinase C zeta (PKC zeta) is a member of the PKC family of enzymes and is involved in a wide range of physiological processes including mitogenesis, protein synthesis, cell survival and transcriptional regulation. PKC zeta has received considerable attention recently as a target of phosphoinositide 3-kinase (PI 3-kinase), although the mechanism of PKC zeta activation is, as yet, unknown. Recent reports have also shown that the phosphoinositide-dependent protein kinase-l (PDK-1), which binds with high affinity to the PI 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (Ptdlns-3,4,5-P-3), phosphorylates and potently activates two other PI 3-kinase targets, the protein kinases Akt/PKB and p70S6K, We therefore investigated whether PDK-1 is the kinase that activates PKC zeta, Results: In vivo, PI 3-kinase is both necessary and sufficient to activate PKC zeta. PDK-1 phosphorylates and activates PKC zeta in vivo, and we have shown that this is due to phosphorylation of threonine 410 in the PKC zeta activation loop. In vitro, PDK-1 phosphorylates and activates PKC zeta in a Ptdlns-3,4,5-P-3-enhanced manner. PKC zeta and PDK-1 are associated in vivo, and membrane targeting of PKC zeta renders it constitutively active in cells, Conclusions: Our results have identified PDK-1 as the kinase that phosphorylates and activates PKC zeta in the PI 3-kinase signaling pathway. This phosphorylation and activation of PKC zeta by PDK-1 is enhanced in the presence of Ptdlns-3,4-5-P-3. Consistent with the notion that PKCs are enzymes that are regulated at the plasma membrane, a membrane-targeted PKC zeta is constitutively active in the absence of agonist stimulation. The association between PKC zeta and PDK-1 reveals extensive cross-talk between enzymes in the PI 3-kinase signaling pathway.
引用
收藏
页码:1069 / 1077
页数:9
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