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The phosphatase PHLPP1 is a key regulator of insulin signaling in vivo
Author(s) -
O’Neill Audrey Kathleen,
Gao Tianyan,
Reyes Gloria,
Newton Alexandra
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1049.1
Subject(s) - protein kinase b , akt2 , akt1 , phosphatase , phosphorylation , medicine , biology , endocrinology , microbiology and biotechnology , chemistry
The recently discovered PHLPP phosphatases, PHLPP1 and PHLPP2, control the amplitude and duration of signaling by Akt by directly dephosphorylating and thus inactivating all three Akt isoforms, Akt1, Akt2, and Akt3. The three Akt isozymes are selectively regulated by the two PHLPP isoforms: Akt1 is complexed with, and dephosphorylated by, PHLPP2; Akt2 is complexed with, and dephosphoryalted by, PHLPP1, and Akt3 is regulated by both PHLPP isoforms. To explore the in vivo role of PHLPP in Akt signaling, we have disrupted the PHLPP1 locus in mice. Mouse embryonic fibroblasts derived from PHLPP1 −/− mice display increased proliferation rates and enhanced insulin sensitivity. Specifically, insulin‐evoked phosphorylation of Akt is increased three‐fold in PHLPP1 −/− MEFs compared to +/+ MEFs. Histological analysis reveals that the pancreatic islets of PHLPP1 −/− mice are markedly smaller and considerably more apoptotic than those of their wild‐type littermates. Thus, lack of PHLPP1 results in enhanced insulin sensitivity and causes defects in β‐cell survival. These data are consistent with PHLPP1's regulation of Akt2, the predominant Akt isoform in insulin‐sensitive tissues. This work was supported by NIH 067946.