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RET/PTC (Rearranged in Transformation/Papillary Thyroid Carcinomas) Tyrosine Kinase Phosphorylates and Activates Phosphoinositide-Dependent Kinase 1 (PDK1): An Alternative Phosphatidylinositol 3-Kinase-Independent Pathway to Activate PDK1

Laboratory of Endocrine Cell Biology (D.W.K., J.H.H., J.M.S., H.K., J.H.S., E.S.H., I.Y.H., K.C.P., H.K.C., M.S.), National Research Laboratory Program, Department of Internal Medicine; Department of Pathology (J.M.K.), Chungnam National University School of Medicine, Daejeon, Korea; and Friedrich Miescher Institute (J.P., M.S.), Basel CH-4058, Switzerland

Address all correspondence and requests for reprints to: Minho Shong, Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University College of Medicine, 640 Daesadong Chungku Daejeon 301-721, Korea. E-mail: minhos{at}cnu.ac.kr.

Thyroid cancers are a leading cause of death due to endocrine malignancies. RET/PTC (rearranged in transformation/papillary thyroid carcinomas) gene rearrangements are the most frequent genetic alterations identified in papillary thyroid carcinoma. Although the oncogenic potential of RET/PTC is related to intrinsic tyrosine kinase activity, the substrates for this enzyme are yet to be identified. In this report, we show that phosphoinositide-dependent kinase 1 (PDK1), a pivotal serine/threonine kinase in growth factor-signaling pathways, is a target of RET/PTC. RET/PTC and PDK1 colocalize in the cytoplasm. RET/PTC phosphorylates a specific tyrosine (Y9) residue located in the N-terminal region of PDK1. Y9 phosphorylation of PDK1 by RET/PTC requires an intact catalytic kinase domain. The short (iso 9) and long forms (iso 51) of the RET/PTC kinases (RET/PTC1 and RET/PTC3) induce Y9 phosphorylation of PDK1. Moreover, Y9 phosphorylation of PDK1 by RET/PTC does not require phosphatidylinositol 3-kinase or Src activity. RET/PTC-induced phosphorylation of the Y9 residue results in increased PDK1 activity, decrease of cellular p53 levels, and repression of p53-dependent transactivation. In conclusion, RET/PTC-induced tyrosine phosphorylation of PDK1 may be one of the mechanisms by which it acts as an oncogenic tyrosine kinase in thyroid carcinogenesis.

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