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Laboratory of Endocrine Cell Biology (H.S.J., D.W.K., Y.S.J., H.K.C., J.H.S., K.C.P., S.H.P., J.H.H., M.S.), National Research Laboratory Program, Department of Internal Medicine, and Department of Pharmacology (J.S.P.), Chungnam National University School of Medicine, Daejeon 301-721; and Life Science R & D (K.-W.J.), LGLS Ltd., Yuseong-Gu, Daejeon 305-380, Korea
Address all correspondence and requests for reprints to: Minho Shong, Laboratory of Endocrine Cell Biology Department of Internal Medicine Chungnam National University School of Medicine, 640 Daesadong Chungku, Daejeon 301-721 Korea. E-mail: minhos{at}cnu.ac.kr.
Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.
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