Insulin stimulates fibroblast proliferation through calcium-calmodulin-dependent kinase II.
Insulin effects are mediated by multiple integrated signals generated by the insulin receptor. Fibroblasts, as most of mammalian cells, are a target of insulin action and are important actors in the vascular pathogenesis of hyperinsulinemia. A role for calcium-calmodulin-dependent kinases (CaMK) in insulin signaling has been proposed but has been under investigated. We investigated the role of the CaMK isoform II in insulin signaling in human fibroblasts. A rapid and transient increase of intracellular calcium concentration was induced by insulin stimulation, followed by increase of CaMKII activity, via L type calcium channels. Concomitantly, insulin stimulation induced Raf-1 and ERK activation, followed by thymidine uptake. Inhibition of CaMKII abrogated the insulin-induced Raf-1 and ERK activation, resulting also in the inhibition of thymidine incorporation. These results demonstrate that in fibroblasts, insulin-activated CaMKII is necessary, together with Raf-1, for ERK activation and cell proliferation. This represents a novel mechanism in the control of insulin signals leading to fibroblast proliferation, as well as a putative site for pharmacological intervention.
Monaco
Sara
S
Department of Biologia e Patologia Cellulare e Molecolare, University of Naples Federico II, Naples, Italy.
Illario
Maddalena
M
Rusciano
Maria Rosaria
MR
Gragnaniello
Giovanni
G
Di Spigna
Gaetano
G
Leggiero
Eleonora
E
Pastore
Lucio
L
Fenzi
Gianfranco
G
Rossi
Guido
G
Vitale
Mario
M
D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
D020746:Calcium Channels, L-Type; D007328:Insulin; D011972:Receptor, Insulin; D019908:Proto-Oncogene Proteins c-raf; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium