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Pleiotropic effects of PHLPP on cell signaling
Author(s) -
Reyes Gloria Ximena,
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.1048.14
Subject(s) - protein kinase b , microbiology and biotechnology , phosphorylation , biology , signal transduction , mapk/erk pathway , phosphatase , pten , pi3k/akt/mtor pathway
The PH domain Leucine Repeat Protein Phosphatases PHLPP1 and PHLPP2 were discovered in a directed search for phosphatases that directly dephosphorylate and inactivate Akt, a key controller of many cellular processes such as cell survival, cell death, proliferation, and motility. Given the relative paucity of phosphatases compared to the abundance of phosphorylated sequences in cells, we asked whether the PHLPP phosphatases controlled additional signaling networks to the Akt pathway. To this end, we used siRNA to deplete PHLPPs from diverse cell lines and analyzed substrates phosphorylated downstream of growth factors such as EGF, PDGF, insulin and TGF‐beta. We found that genetic depletion of PHLPP isoforms dramatically increased agonist‐evoked signaling by each of these agonists. The effects of PHLPP knockdown depended on the tumorigenic state of the cell lines and the growth factor used. Importantly, PHLPP knockdown affected not only Akt phosphorylation, but also the phosphorylation of substrates which are modulated by distinct pathways from Akt, such as those involving the MAPK and SMAD proteins. These findings reveal differential and/or synergistic contributions of PHLPP isoforms to suppressing signaling in numerous cellular pathways, revealing an important pleiotropic role of these phosphatases on cell signaling. This work was funded by NIH GM NIH 067946