Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src SH2 domain binding

doi:10.1074/jbc.M706361200

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Papers In Press, published online ahead of print November 16, 2007
J. Biol. Chem, 10.1074/jbc.M706361200
Submitted on August 1, 2007
Revised on November 14, 2007
Accepted on November 16, 2007

Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src SH2 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, Brian A. Hemmings, and Jongsun Park

Dep of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, Daejeon 301-101

Corresponding Author: insulin{at}cnu.ac.kr

3-Phosphoinositide-dependent protein kinase-1 (PDK1) appears to play a central regulatory role in many cell-signaling 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 Tyr373/376) following the treatment of 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 towards to PKB and SGK. Immunohistochemical analysis with anti-phospho-Tyr9 antibodies showed that the level of Tyr9 phosphorylation was markedly increased in tumor samples compared to normal. Taken together, these data suggest that phosphorylation of PDK1 on Tyr9, distinct from Tyr373/376, 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.

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