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J. Biol. Chem., Vol. 276, Issue 52, 48627-48630, December 28, 2001
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,
From the Department of Adult Oncology, Dana-Farber Cancer Institute
and Department of Medicine, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115
PTEN is a tumor suppressor protein that
functions, in large part, by dephosphorylating the lipid second
messenger phosphatidylinositol 3,4,5-trisphosphate and by doing
so antagonizing the action of phosphoinositide 3-kinase. PTEN
structural domains include an N-terminal phosphatase domain, a
lipid-binding C2 domain, and a 50-amino acid C-terminal tail that
contains a PDZ binding sequence. We showed previously that
phosphorylation of the PTEN tail negatively regulates PTEN activity. We
now show that phosphorylated PTEN exists in a monomeric "closed"
conformation and has low affinity for PDZ domain-containing proteins.
Conversely, when unphosphorylated, PTEN is in an "open"
conformation, is recruited into a high molecular weight complex
(PTEN-associated complex), and strongly interacts with PDZ-containing
proteins such as MAGI-2. As a consequence, when compared with
wild-type PTEN, the phosphorylation-deficient mutant form of PTEN
strongly cooperates with MAGI-2 to block Akt activation. These results
indicate that phosphorylation of the PTEN tail causes a conformational
change that results in the masking of the PDZ binding domain.
Consequently, the ability of PTEN to bind to PDZ
domain-containing proteins is reduced dramatically. These data suggest
that phosphorylation of the PTEN tail suppresses the activity of PTEN
by controlling the recruitment of PTEN into the PTEN-associated complex.
Supported by a grant from the Department of Defense
Prostate Cancer Research Program.
§
Supported by grants from the National Institutes of
Health, the DOD-PCRP, Association for the Cure of Cancer of the
Prostate (CaP CURE), and the Gillette Women's Cancer Program. To whom
correspondence should be addressed. E-mail:
William_Sellers@dfci.harvard.edu.
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