Serum withdrawal-induced accumulation of phosphoinositide 3-kinase lipids in differentiating 3T3-L6 myoblasts: distinct roles for Ship2 and PTEN.

Mandl A, Sarkes D, Carricaburu V, Jung V, Rameh L
Mol Cell Biol. 2007 27 (23): 8098-112

PMID: 17893321 · PMCID: PMC2169165 · DOI:10.1128/MCB.00756-07

Phosphoinositide 3-kinase (PI3K) activation and synthesis of phosphatidylinositol-3,4-bisphosphate (PI-3,4-P2) and phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3) lipids mediate growth factor signaling that leads to cell proliferation, migration, and survival. PI3K-dependent activation of Akt is critical for myoblast differentiation induced by serum withdrawal, suggesting that in these cells PI3K signaling is activated in an unconventional manner. Here we investigate the mechanisms by which PI3K signaling and Akt are regulated during myogenesis. We report that PI-3,4-P2 and PI-3,4,5-P3 accumulated in the plasma membranes of serum-starved 3T3-L6 myoblasts due to de novo synthesis and increased lipid stability. Surprisingly, only newly synthesized lipids were capable of activating Akt. Knockdown of the lipid phosphatase PTEN moderately increased PI3K lipids but significantly increased Akt phosphorylation and promoted myoblast differentiation. Knockdown of the lipid phosphatase Ship2, on the other hand, dramatically increased the steady-state levels of PI-3,4,5-P3 but did not affect Akt phosphorylation and increased apoptotic cell death. Together, these results reveal the existence of two distinct pools of PI3K lipids in differentiating 3T3-L6 myoblasts: a pool of nascent lipids that is mainly dephosphorylated by PTEN and is capable of activating Akt and promoting myoblast differentiation and a stable pool that is dephosphorylated by Ship2 and is unable to activate Akt.

MeSH Terms (23)

Animals Catalysis Cell Differentiation Cell Proliferation Cell Survival HeLa Cells Humans Inositol Polyphosphate 5-Phosphatases Insulin Mice Mutant Proteins Myoblasts Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases Phosphatidylinositol 3-Kinases Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Phosphoric Monoester Hydrolases Phosphorylation Protein Structure, Tertiary Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Rats Serum

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