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Direct identification of PTEN phosphorylation sites
Author(s) -
Miller Susan J.,
Lou David Y.,
Seldin David C.,
Lane William S.,
Neel Benjamin G.
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)03274-x
Subject(s) - pten , phosphorylation , cancer research , protein kinase b , phosphatase , pi3k/akt/mtor pathway , chemistry , carcinogenesis , biology , microbiology and biotechnology , signal transduction , biochemistry , gene
The PTEN tumor suppressor gene encodes a phosphatidylinositol 3′‐phosphatase that is inactivated in a high percentage of human tumors, particularly glioblastoma, melanoma, and prostate and endometrial carcinoma. Previous studies showed that PTEN is a seryl phosphoprotein and a substrate of protein kinase CK2 (CK2). However, the sites in PTEN that are phosphorylated in vivo have not been identified directly, nor has the effect of phosphorylation on PTEN catalytic activity been reported. We used mass spectrometric methods to identify Ser 370 and Ser 385 as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr 366 . Following transient over‐expression, a fraction of CK2 and PTEN co‐immunoprecipitate. Moreover, pharmacological inhibition of CK2 activity leads to decreased Akt activation in PTEN+/+ but not PTEN−/− fibroblasts. Our results contrast with previous assignments of PTEN phosphorylation sites based solely on mutagenesis approaches, suggest that CK2 is a physiologically relevant PTEN kinase, and raise the possibility that CK2‐mediated inhibition of PTEN plays a role in oncogenesis.