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J. Biol. Chem., Vol. 283, Issue 3, 1480-1491, January 18, 2008

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Regulation of 3-Phosphoinositide-dependent Protein Kinase-1 (PDK1) by Src Involves Tyrosine Phosphorylation of PDK1 and Src Homology 2 Domain Binding^*

Keum-Jin Yang, Sanghee Shin, Longzhen Piao, Eulsoon Shin, Yuwen Li, Kyeong Ah Park, Hee Sun Byun, Minho Won, Janghee Hong, Gi Ryang Kweon, Gang Min Hur, Jeong Ho Seok, Taehoon Chun^¶, Derek P. Brazil^||1, Brian A. Hemmings^**, and Jongsun Park²

From the Department of Pharmacology, Daejeon Regional Cancer Center, Cancer Research Institute, Research Institute for Medical Sciences, and the Department of Biochemistry, College of Medicine, Chungnam National University, Taejeon 301-131, South Korea, ^¶Division of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea, ^||University College Dublin School of Biomolecular and Biomedical Science, University College Dublin Conway Institute, University College Dublin, Dublin 4, Ireland, and the ^**Friedrich Miescher Institute for Biomedical Research, Basel CH-4058, Switzerland

3-Phosphoinositide-dependent protein kinase-1 (PDK1) appears to play a central regulatory role in many cell signalings between phosphoinositide-3 kinase and various intracellular serine/threonine kinases. In resting cells, PDK1 is known to be constitutively active and is further activated by tyrosine phosphorylation (Tyr⁹ and Tyr^373/376) following the treatment of the cell with insulin or pervanadate. However, little is known about the mechanisms for this additional activation of PDK1. Here, we report that the SH2 domain of Src, Crk, and GAP recognized tyrosine-phosphorylated PDK1 in vitro. Destabilization of PDK1 induced by geldanamycin (a Hsp90 inhibitor) was partially blocked in HEK 293 cells expressing PDK1-Y9F. Co-expression of Hsp90 enhanced PDK1-Src complex formation and led to further increased PDK1 activity toward PKB and SGK. Immunohistochemical analysis with anti-phospho-Tyr⁹ antibodies showed that the level of Tyr⁹ phosphorylation was markedly increased in tumor samples compared with normal. Taken together, these data suggest that phosphorylation of PDK1 on Tyr⁹, distinct from Tyr^373/376, is important for PDK1/Src complex formation, leading to PDK1 activation. Furthermore, Tyr⁹ phosphorylation is critical for the stabilization of both PDK1 and the PDK1/Src complex via Hsp90-mediated protection of PDK1 degradation.

Received for publication, August 1, 2007 , and in revised form, November 14, 2007.

^* This work was supported in part by Science Research Center/Engineering Research Center Program Grant R11-2002-100-02006-0 and Basic Research Program Grants R01-2005-000-10240-0 and F01-2005-000-10011-0 of the Korea Science and Engineering Foundation, funded by the government of Korea, and by National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea, Grant 0720560. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Work in the laboratory of this author was supported by Science Foundation Ireland and the Irish Health Research Board.

² To whom correspondence should be addressed: Dept. of Pharmacology, College of Medicine, Chungnam National University, 6 Munhwa-Dong, Jung-Gu, Taejeon 301-131, South Korea. Tel.: 82-42-580-8252; Fax: 82-42-585-6627; E-mail: insulin{at}cnu.ac.kr.

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