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PDK1‐dependent activation of atypical PKC leads to degradation of the p21 tumour modifier protein
Author(s) -
Scott Mary T.,
Ingram Angela,
Ball Kathryn L.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf684
Subject(s) - biology , kinase , microbiology and biotechnology , protein kinase c , phosphatidylinositol , protein kinase a , phosphorylation , protein degradation , proteasome , cyclin dependent kinase 2 , biochemistry
p21 WAF1/CIP1 contributes to positive and negative growth control on multiple levels. We previously mapped phosphorylation sites within the C‐terminal domain of p21 that regulate proliferating cell nucear antigen binding. In the current study, a kinase has been fractionated from mammalian cells that stoichiometrically phosphorylates p21 at the Ser146 site, and the enzyme has been identified as an insulin‐responsive atypical protein kinase C (aPKC). Expression of PKCζ or activation of the endogenous kinase by 3‐phosphoinositide dependent protein kinase‐1 (PDK1) decreased the half‐life of p21. Conversely, dnPKCζ or dnPDK1 increased p21 protein half‐life, and a PDK1‐dependent increase in the rate of p21 degradation was mediated by aPKC. Insulin stimulation gave a biphasic response with a rapid transient decrease in p21 protein levels during the initial signalling phase that was dependent on phosphatidylinositol 3‐ kinase, PKC and proteasome activity. Thus, aPKC provides a physiological signal for the degradation of p21. The rapid degradation of p21 protein during the signalling phase of insulin stimulation identifies a novel link between energy metabolism and a key modulator of cell cycle progression.