title: Neuregulin signaling on glucose transport in muscle cells.
abstract: 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-beta(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 PKBalpha, PKBgamma, and PKCzeta 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 PKBalpha. 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 PKCzeta abolished both HRG- and insulin-stimulated glucose uptake. In soleus muscle, HRG induced PKCzeta, 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 AMPKalpha(1) or AMPKalpha(2) activities. In all, HRG stimulated glucose transport in muscle cells by activation of a pathway that requires PI3K, PDK1, and PKCzeta, but not PKB, and that shows cross-talk with the MAPK pathway. The PI3K, PDK1, and PKCzeta pathway can be considered as an alternative mechanism, independent of insulin, to induce glucose uptake.
authors.affiliation: Departament de Bioquímica i Biologia Molecular and Parc Científic de Barcelona, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Cantó
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Suárez
authors.forename: José M
authors.initials: JM
authors.lastname: Lizcano
authors.forename: Elisenda
authors.initials: E
authors.lastname: Griñó
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.forename: Lee G D
authors.initials: LG
authors.lastname: Fryer
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.forename: Joan
authors.initials: J
authors.lastname: Bertran
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: Anna
authors.initials: A
authors.lastname: Gumà
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000256:Adenoviridae / Q000235:genetics; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D015151:Immunoblotting; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000263:Adenylate Kinase; D004791:Enzyme Inhibitors; D005947:Glucose; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020890:Neuregulin-1; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D014108:Tosylphenylalanyl Chloromethyl Ketone; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta; C111490:Akt3 protein, rat; C578579:Pdpk1 protein, rat