The Ca2+-calmodulin dependent kinase II (CaMKII) is activated in papillary thyroid carcinoma and mediates cell proliferation stimulated by RET/PTC.

RET/PTC, TRK-T or activating mutations of Ras and BRaf, are frequent genetic alterations in thyroid papillary cancer (PTC), all leading to the activation of the Erk cascade. Aim of this study was to investigate the role of 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 harbouring the oncogenes RET/PTC-1 or BRafV600E, CaMKII was active also in the absence of any stimulation. Inhibition of calmodulin or phospholipase C attenuated the level of CaMKII activation. Expression of recombinant RET/PTC-3, BRafV600E or RasV12 induced CaMKII activation. Inhibition of CaMKII attenuated Erk activation and DNA synthesis in TPC-1, a cell line harbouring RET/PTC-1, suggesting that CaMKII is a component of the Erk signal cascade in this cell line. In conclusion, thyroid papillary carcinomas harbour an active phospholipase C/Ca2+/calmodulin-dependent signal inducing constitutive activation of CaMKII. This kinase is activated by BRafV600E, 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.