PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts.
Catalytic subunits of phosphoinositide-3-kinase (PI3K) play a critical role in growth factor signaling and survival by phosphorylating inositol lipids. We found that PI3K Class-IA p110 alpha and p110 beta have distinct functions in myoblasts. Inhibition of p110 alpha reduced insulin-like growth factor-I (IGF-I)-stimulated Akt activity and prevented IGF-I-mediated survival in H(2)O(2)-treated cells; in contrast, siRNA knockdown of p110 beta increased IGF-I-stimulated Akt activity. However, inhibition of p110 beta catalytic activity did not increase IGF-I-stimulated Akt activity, suggesting a role for p110 beta protein interactions rather than decreased generation of phosphoinositides in this effect. Increased Akt activity in p110 beta-deficient myoblasts was associated with diminished extracellular signal-regulated kinase (ERK) activation as well as ERK-dependent IRS-1 636/639 phosphorylation, findings we show to be independent of p110 beta catalytic function, but associated with insulin-like growth factor-I receptor (IGF-IR) endocytosis. We also report that IGF-I protects myoblasts from H(2)O(2)-induced apoptosis through a mechanism that requires p110 alpha, but may be independent of Akt or ERK under conditions of Akt and ERK inhibition. These observations suggest that both p110 alpha and p110 beta are essential for growth and metabolism in myoblasts. Overall, our results provide new evidence for the roles of p110 isoforms in promoting cellular proliferation and homeostasis, IGF-IR internalization, and in opposing apoptosis.
Matheny
R W
RW
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Adamo
M L
ML
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D019610:Cytoprotection / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006861:Hydrogen Peroxide / Q000633:toxicity; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000378:metabolism
D007527:Isoenzymes; D016877:Oxidants; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases