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This version published online on September 18, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0261
Molecular Endocrinology Vol. 0, No. 2003 200302611-
doi:10.1210/me.2003-0261
Copyright © 2003 by the Endocrine Society.
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Submitted on July 3, 2003
Accepted on September 8, 2003

Expression of myotubularin by an adenoviral vector demonstrates its function as a PtdIns(3)P phosphatase in muscle cell lines. Involvement of PtdIns(3)P in insulin-stimulated glucose transport

Claire Chaussade1, Luciano Pirola1, Stéphanie Bonnafous1, François Blondeau1, Stefano Brenz-Verca1, Hélène Tronchère1, Fiorella Portis1, Sandro Rusconi1, Bernard Payrastre1, Jocelyn Laporte1, and E Van Obberghen1*

1 INSERM U145, IFR50, Faculté de Médecine, 06107 Nice Cedex 2, France, IGBMC, 67404 Illkirch, France, Institute of Biochemistry, University of Fribourg, CH-1700, Switzerland, INSERM U326, Hopital Purpan, 31059 Toulouse, France

* To whom correspondence should be addressed. E-mail: vanobbeg{at}unice.fr.

X-linked myotubular myopathy is a muscle disorder caused by mutations on the MTM-1 gene, coding for myotubularin-a 65 kDa polypeptide similar to protein phosphatases. Biochemical and in vivo studies define myotubularin as a phosphatidylinositol 3-phosphate (PtdIns(3)P) phosphatase. To efficiently express myotubularin in muscle cell lines and adipocytes, we used an adenoviral genome recombinogenic to pcDNA3 - and other widely used expression vectors - to produce adenoviruses expressing wild-type (wt), catalytically inactive C375S and substrate trapping D278A myotubularin.

[32P] orthophosphate labeling followed by phosphoinositide analysis of differentiated L6 and C2C12 cells expressing myotubularin demonstrated increased PtdIns(3)P levels upon expression of the C375S and D278A mutants. In keep with its biochemical function, overexpression of wt myotubularin as an EGFP fusion disrupted the endosomal punctuated staining of the FYVE-domain-containing PtdIns(3)P binding protein early endosomal antigen 1 (EEA1) as well as of a GST-FYVE probe directed to PtdIns(3)P. Expression of wt myotubularin, while not affecting activation of proximal insulin signal transduction targets such as PKB and MAPK, induced a decrease in insulin-induced glucose uptake, while basal glucose uptake was augmented by expression of DA and CS mutants. Moreover, overexpression in 3T3-L1 adipocytes of myotubularin impaired insulin-induced translocation at the plasma membrane of GFP tagged GLUT4. These data indicate that PtdIns(3)P is required to direct GLUT4 to insulin responsive compartments and/or to allow the translocation of the latter at the plasma membrane.

We conclude that myotubularin, by modulating the intracellular levels of PtdIns(3)P, plays a role in the control of vesicular traffic related to glucose transport, by counteracting the activities of the PtdIns(3)P -producing PI 3-kinases.
Key words: myotubularin • muscle cells • PtdIns(3)P • vesicular trafficking • insulin • glucose uptake




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