Abstract
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 p110α and p110β have distinct functions in myoblasts. Inhibition of p110α reduced insulin-like growth factor-I (IGF-I)-stimulated Akt activity and prevented IGF-I-mediated survival in H2O2-treated cells; in contrast, siRNA knockdown of p110β increased IGF-I-stimulated Akt activity. However, inhibition of p110β catalytic activity did not increase IGF-I-stimulated Akt activity, suggesting a role for p110β protein interactions rather than decreased generation of phosphoinositides in this effect. Increased Akt activity in p110β-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 p110β catalytic function, but associated with insulin-like growth factor-I receptor (IGF-IR) endocytosis. We also report that IGF-I protects myoblasts from H2O2-induced apoptosis through a mechanism that requires p110α, but may be independent of Akt or ERK under conditions of Akt and ERK inhibition. These observations suggest that both p110α and p110β 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.
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Abbreviations
- PI3K:
-
phosphoinositide-3-kinase
- IGF-I:
-
insulin-like growth factor-I
- IGF-IR:
-
insulin-like growth factor-I receptor
- ERK:
-
extracellular signal-regulated kinase
- MEK:
-
mitogen-activated ERK kinase
- IRS-1:
-
insulin receptor substrate-1
- PARP:
-
poly-(ADP)-ribosyl polymerase.
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Acknowledgements
We thank Dr John C Lee of the Department of Biochemistry, University of Texas Health Science Center at San Antonio, for many helpful discussions during the preparation of this work. This work was supported by NIA grant R01AG026012 to MLA. RWM was supported by pre-doctoral award from NIA training grant T32 AG021890-08.
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Matheny, R., Adamo, M. PI3K p110α and p110β have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts. Cell Death Differ 17, 677–688 (2010). https://doi.org/10.1038/cdd.2009.150
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DOI: https://doi.org/10.1038/cdd.2009.150
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