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This version published online on May 8, 2003
Molecular Endocrinology, doi:10.1210/me.2002-0402
Molecular Endocrinology Vol. 0, No. 2003 200204021-
doi:10.1210/me.2002-0402
Copyright © 2003 by the Endocrine Society.
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*Compound via MeSH
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*L-TYROSINE

Submitted on December 4, 2002
Accepted on April 16, 2003

RET/PTC TYROSINE KINASE PHOSPHORYLATES AND ACTIVATES PHOSPHOINOSITIDE-DEPENDENT KINASE 1 (PDK1): AN ALTERNATIVE PI3K-INDEPENDENT PATHWAY TO ACTIVATE PDK1

Dong Wook Kim1, Jung Hwan Hwang1, Jae Mi Suh1, Ho Kim1, Jung Hun Song1, Eun Suk Hwang1, Il Young Hwang1, Ki Cheol Park1, Hyo Kyun Chung1, Jin Man Kim1, Jongsun Park1, Brian A. Hemmings1, and Minho Shong1*

1 Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine; Department of Pathology, Chungnam National University School of Medicine, Daejeon, Korea; Friedrich Miescher Institute, Maulbeerstrasse 66, Basel CH-4058, Switzerland

* To whom correspondence should be addressed. E-mail: minhos{at}cnu.ac.kr.

Thyroid cancers are a leading cause of death due to endocrine malignancies. RET/PTC 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 PDK1, a pivotal serine/threonine kinase in growth factor signaling pathways, is a target of RET/PTC. RET/PTC and PDK1 co-localize 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 PI3K 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 through which it acts as an oncogenic tyrosine kinase in thyroid carcinogenesis.




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