Myotubularin regulates Akt-dependent survival signaling via phosphatidylinositol 3-phosphate

Gina Razidlo, Dawn Katafiasz, Gregory S. Taylor

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Myotubularin is a 3-phosphoinositide phosphatase that is mutated in X-linked myotubular myopathy, a severe neonatal disorder in which skeletal muscle development and/or regeneration is impaired. In this report we provide evidence that siRNA-mediated silencing of myotubularin expression markedly inhibits growth factor-stimulated Akt phosphorylation, leading to activation of caspase-dependent pro-apoptotic signaling in HeLa cells and primary human skeletal muscle myotubes. Myotubularin silencing also inhibits Akt-dependent signaling through the mammalian target of rapamycin complex 1 as assessed by p70 S6-kinase and 4E-BP1 phosphorylation. Similarly, phosphorylation of FoxO transcription factors is also significantly reduced in myotubularin-deficient cells. Our data further suggest that inhibition of Akt activation and downstream survival signaling in myotubularin-deficient cells is caused by accumulation of the MTMR substrate lipid phosphatidylinositol 3-phosphate generated from the type II phosphatidylinositol 3-kinase PIK3C2B. Our findings are significant because they suggest that myotubularin regulates Akt activation via a cellular pool of phosphatidylinositol 3-phosphate that is distinct from that generated by the type III phosphatidylinositol 3-kinase hVps34. Because impaired Akt signaling has been tightly linked to skeletal muscle atrophy, we hypothesize that loss of Akt-dependent growth/survival cues due to impaired myotubularin function may be a critical factor underlying the severe skeletal muscle atrophy characteristic of muscle fibers in patients with X-linked myotubular myopathy.

Original languageEnglish (US)
Pages (from-to)20005-20019
Number of pages15
JournalJournal of Biological Chemistry
Volume286
Issue number22
DOIs
StatePublished - Jun 3 2011

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Muscle
Survival
Phosphorylation
Skeletal Muscle
Congenital Structural Myopathies
Phosphatidylinositol 3-Kinase
Muscular Atrophy
Chemical activation
70-kDa Ribosomal Protein S6 Kinases
Muscle Development
Skeletal Muscle Fibers
Caspases
Phosphatidylinositols
phosphatidylinositol 3-phosphate
myotubularin
HeLa Cells
Phosphoric Monoester Hydrolases
Small Interfering RNA
Cues
Regeneration

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Myotubularin regulates Akt-dependent survival signaling via phosphatidylinositol 3-phosphate. / Razidlo, Gina; Katafiasz, Dawn; Taylor, Gregory S.

In: Journal of Biological Chemistry, Vol. 286, No. 22, 03.06.2011, p. 20005-20019.

Research output: Contribution to journalArticle

Razidlo, Gina ; Katafiasz, Dawn ; Taylor, Gregory S. / Myotubularin regulates Akt-dependent survival signaling via phosphatidylinositol 3-phosphate. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 22. pp. 20005-20019.
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