title: Calcium-calmodulin-dependent kinase II (CaMKII) mediates insulin-stimulated proliferation and glucose uptake.
abstract: Cellular growth and glucose uptake are regulated by multiple signals generated by the insulin receptor. The mechanisms of individual modulation of these signals remain somewhat elusive. We investigated the role of CaMKII in insulin signalling in a rat skeletal muscle cell line, demonstrating that CaMKII modulates the insulin action on DNA synthesis and the negative feedback that down regulates glucose uptake. Insulin stimulation generated partly independent signals leading to the rapid activation of Akt, Erk-1/2 and CaMKII. Akt activation was followed by Glut-4 translocation to the plasma membrane and increase of glucose uptake. Then, IRS-1 was phosphorylated at S612, the IRS-1/p85PI3K complex was disrupted, Akt was no more phosphorylated and both Glut-4 translocation and glucose uptake were reduced. Inhibition of CaMKII abrogated the insulin-induced Erk-1/2 activation, DNA synthesis and phosphorylation of IRS-1 at S612. Inhibition of CaMKII also abrogated the down-regulation of insulin-stimulated Akt phosphorylation, Glut-4 membrane translocation and glucose uptake. These results demonstrate that: 1 - CaMKII modulates the insulin-induced Erk-1/2 activation and cell proliferation; 2 - after the initial stimulation of the IRS-1/Akt pathway, CaMKII mediates the down-regulation of stimulated glucose uptake. This represents a novel mechanism in the selective control of insulin signals, and a possible site for pharmacological intervention.
authors.affiliation: Department of Biologia e Patologia Cellulare e Molecolare, University of Naples Federico II, Naples, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Illario
authors.forename: Sara
authors.initials: S
authors.lastname: Monaco
authors.forename: Anna Lina
authors.initials: AL
authors.lastname: Cavallo
authors.forename: Iolanda
authors.initials: I
authors.lastname: Esposito
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Luca
authors.initials: L
authors.lastname: D'Andrea
authors.forename: Ersilia
authors.initials: E
authors.lastname: Cipolletta
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Fenzi
authors.forename: Guido
authors.initials: G
authors.lastname: Rossi
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
mesh_terms: D000818:Animals; D001692:Biological Transport; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D004247:DNA; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose