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Submitted on March 14, 2005
Accepted on June 13, 2005
Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine; Department of Pharmacology, Chungnam National University School of Medicine, Daejeon, 301-721, Korea; Life Science R & D, LGLS Ltd. 104-1 Moonji-dong, Yuseong-Gu, Daejeon, 305-380, Korea
* To whom correspondence should be addressed. 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 PDK-1 and PDK-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 sum, 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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