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Fibronectin-Induced Proliferation in Thyroid Cells Is Mediated by vß3 Integrin through Ras/Raf-1/MEK/ERK and Calcium/CaMKII Signals

Departments of Biologia e Patologia Cellulare e Molecolare (M.I., A.L.C., S.M., E.D.V., G.R.), Endocrinologia ed Oncologia Molecolare e Clinica (F.M., G.F., M.V.), and Scienze Biomorfologiche e Funzionali (G.T.), and Unit of Endocrine and General Surgery (L.A.M.), Università Federico II, 80131 Naples, Italy; and Institute of Endocrinologia ed Oncologia Sperimentale "G. Salvatore" (G.R.), Consiglio Nazionale delle Ricerche, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Mario Vitale, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Via S. Pansini, 5 Napoli, 80131 Italy. E-mail: mavitale{at}unina.it.

We recently demonstrated in an immortalized thyroid cell line that integrin stimulation by fibronectin (FN) simultaneously activates two signaling pathways: Ras/Raf/MAPK kinase (Mek)/Erk and calcium (Ca²⁺)/calcium calmodulin-dependent kinase II (CaMKII). Both signals are necessary to stimulate Erk phosphorylation because CaMKII modulates Ras-induced Raf-1 activity. In this study we present evidence that extends these findings to normal human thyroid cells in primary culture, demonstrating its biological significance in a more physiological cell model. In normal thyroid cells, immobilized FN-induced activation of p21Ras and Erk phosphorylation. This pathway was responsible for FN-induced cell proliferation. Concurrent increase of intracellular Ca²⁺ concentration and CaMKII activation was observed. Both induction of p21Ras activity and increase of intracellular Ca²⁺ concentration were mediated by FN binding to vß3 integrin. Inhibition of the Ca²⁺/CaMKII signal pathway by calmodulin or CaMKII inhibitors completely abolished the FN-induced Erk phosphorylation. Binding to FN induced Raf-1 and CaMKII to form a protein complex, indicating that intersection between Ras/Raf/Mek/Erk and Ca²⁺/CaMKII signaling pathways occurred at Raf-1 level. Interruption of the Ca²⁺/CaMKII signal pathway arrested cell proliferation induced by FN. We also analyzed thyroid tumor cell lines that displayed concomitant aberrant integrin expression and signal transduction. These data confirm that integrin activation by FN in normal thyroid cells generates Ras/Raf/Mek/Erk and Ca²⁺/CaMKII signaling pathways and that both are necessary to stimulate cell proliferation, whereas in thyroid tumors integrin signaling is altered.

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