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PHLiPPing the Switch in Lipid Second Messenger Signaling
Author(s) -
Newton Alexandra C
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.245.1
Subject(s) - diacylglycerol kinase , protein kinase b , microbiology and biotechnology , second messenger system , protein kinase c , kinase , biology , signal transduction , phosphorylation , protein kinase a , c raf , mitogen activated protein kinase kinase , chemistry
The lipid second messenger‐activated kinases protein kinase C (PKC) and Akt control cell growth, proliferation, and survival. PKC transduces signals that result in diacylglycerol production following, typically, phospholipase C activation; Akt transduces signals that result in generation of 3’‐phosphoinositides catalyzed by PI 3 kinase. Both pathways acutely control the exquisite balance between cell survival and apoptosis. Signaling by these kinases is propagated by two mechanisms: a phosphorylation cascade triggered by the upstream kinase PDK‐1, and binding of the relevant lipid second messenger. Similarly, signaling is terminated by two mechanisms: removal of the activating lipid second messenger and dephosphorylation of the kinase. We have recently identified a novel phosphatase family, PHLPP (for PH domain leucine‐rich repeat protein phosphatase) that directly dephosphorylates Akt and PKC, terminating signaling by these two kinases. In the case of the diacylglycerol pathway, PHLPP controls the amplitude of signaling by controlling the amount of protein kinase C in the cell. In the case of the PI3 kinase pathway, PHLPP controls the amplitude of signaling by controlling the degree of agonist‐evoked phosphorylation of Akt. Thus, the protein phosphatase PHLPP plays a central role in lipid second messenger signaling by directly opposing the function of the protein kinase PDK‐1.