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J. Biol. Chem., Vol. 279, Issue 13, 12260-12268, March 26, 2004

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Neuregulin Signaling on Glucose Transport in Muscle Cells^*

Carles Cantó, Elisabeth Suárez¶, José M. Lizcano||, Elisenda Griñó**, Peter R. Shepherd**, Lee G. D. Fryer, David Carling, Joan Bertran, Manuel Palacín, Antonio Zorzano¶¶, and Anna Gumà||||

From the Departament de Bioquímica i Biologia Molecular and Parc Científic de Barcelona, Universitat de Barcelona, Avda. Diagonal, 645, E-08028 Barcelona, Spain, the ^||MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 4HN, United Kingdom, the ^**Department of Biochemistry, University College of London, Darwin Building, Gower St. WC1E 6BT London, United Kingdom, and the MRC Clinical Sciences Centre, Cellular Stress Group, School of Medicine, Imperial College of London, Hammersmith Hospital, DuCane Road, London W12 0NN, United Kingdom

Neuregulin-1, a growth factor that potentiates myogenesis induces glucose transport through translocation of glucose transporters, in an additive manner to insulin, in muscle cells. In this study, we examined the signaling pathway required for a recombinant active neuregulin-1 isoform (rhHeregulin-₁, 177–244, HRG) to stimulate glucose uptake in L6E9 myotubes. The stimulatory effect of HRG required binding to ErbB3 in L6E9 myotubes. PI3K activity is required for HRG action in both muscle cells and tissue. In L6E9 myotubes, HRG stimulated PKB, PKB, and PKC activities. TPCK, an inhibitor of PDK1, abolished both HRG- and insulin-induced glucose transport. To assess whether PKB was necessary for the effects of HRG on glucose uptake, cells were infected with adenoviruses encoding dominant negative mutants of PKB. Dominant negative PKB reduced PKB activity and insulin-stimulated glucose transport but not HRG-induced glucose transport. In contrast, transduction of L6E9 myotubes with adenoviruses encoding a dominant negative kinase-inactive PKC abolished both HRG- and insulin-stimulated glucose uptake. In soleus muscle, HRG induced PKC, but not PKB phosphorylation. HRG also stimulated the activity of p70S6K, p38MAPK, and p42/p44MAPK and inhibition of p42/p44MAPK partially repressed HRG action on glucose uptake. HRG did not affect AMPK₁ or AMPK₂ activities. In all, HRG stimulated glucose transport in muscle cells by activation of a pathway that requires PI3K, PDK1, and PKC, but not PKB, and that shows cross-talk with the MAPK pathway. The PI3K, PDK1, and PKC pathway can be considered as an alternative mechanism, independent of insulin, to induce glucose uptake.

Received for publication, August 4, 2003 , and in revised form, December 23, 2003.

^* This work was supported by a grant from the Ministerio de Ciencia y Tecnología, SAF2002-01585 (to A. G.) and grants from the Instituto de Salud Carlos III/FIS, G03/212 and C03/08 (to A. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Supported by the Instituto de Salud Carlos III/FIS, G03/212.

^¶ Recipient of a predoctoral fellowship from the Universitat de Barcelona, Spain.

Supported by the Program Ramón y Cajal from the Ministerio de Ciencia y Tecnología, with FEDER/FSE funds, and the University of Barcelona.

^¶¶ To whom correspondence may be addressed. E-mail: azorzano{at}bio.ub.es. |||| Supported by the Program Ramón y Cajal from the Ministerio de Ciencia y Tecnología, with FEDER/FSE funds, and the University of Barcelona. To whom correspondence may be addressed. E-mail: aguma{at}bio.ub.es.

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