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This Article Full Text Full Text (PDF) All Versions of this Article: ERC-09-0214v1 17/1/113    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rusciano, M. R. Articles by Vitale, M. Search for Related Content PubMed PubMed Citation Articles by Rusciano, M. R. Articles by Vitale, M.

¹ Department of Biologia e Patologia Cellulare e Molecolare, Università Federico II, Naples, Italy
² Department of Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II, Naples, Italy
³ Department of Scienze Farmaceutiche, Università di Salerno, Salerno, Italy
⁴ Department of Biochimica e Biotecnologie Mediche, Università Federico II, Naples, Italy
⁵ CEINGE-Biotecnologie Avanzate, Naples, Italy
⁶ CISI, Center for Basic and Clinical Immunological Sciences, Università Federico II, Naples, Italy
⁷ Facoltà di Medicina, Università di Salerno, Salerno, Italy

(Correspondence should be addressed to M Vitale at Department of Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II, Via S. Panini, 5, Naples 80131, Italy; Email: mavitale{at}unina.it)

RET/papillary thyroid carcinoma (PTC), TRK-T, or activating mutations of Ras and BRaf are frequent genetic alterations in PTC, all leading to the activation of the extracellular-regulated kinase (Erk) cascade. The aim of this study was to investigate the role of calmodulin-dependent kinase II (CaMKII) in the signal transduction leading to Erk activation in PTC cells. In normal thyroid cells, CaMKII and Erk were in the inactive form in the absence of stimulation. In primary PTC cultures and in PTC cell lines harboring the oncogenes RET/PTC-1 or BRaf^V600E, CaMKII was active also in the absence of any stimulation. Inhibition of calmodulin or phospholipase C (PLC) attenuated the level of CaMKII activation. Expression of recombinant RET/PTC-3, BRaf^V600E, or Ras^V12 induced CaMKII activation. Inhibition of CaMKII attenuated Erk activation and DNA synthesis in thyroid papillary carcinoma (TPC-1), a cell line harboring RET/PTC-1, suggesting that CaMKII is a component of the Erk signal cascade in this cell line. In conclusion, PTCs contain an active PLC/Ca²⁺/calmodulin-dependent signal inducing constitutive activation of CaMKII. This kinase is activated by BRaf^V600E, oncogenic Ras, and by RET/PTC. CaMKII participates to the activation of the Erk pathway by oncogenic Ras and RET/PTC and contributes to their signal output, thus modulating tumor cell proliferation.