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, Ah Park Kyeong, Sun Byun Hee, Minho Won, Janghee Hong, Ryang Kweon Gi, Min Hur Gang, Ho Seok Jeong, Taehoon Chun, Derek P. Brazil, Brian A. Hemmings, Jongsun Park

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54 Citations (Scopus)

Abstract

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 Tyr373/376) 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 Tyr 9, 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.

Original languageEnglish
Pages (from-to)1480-1491
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number3
DOIs
Publication statusPublished - 2008 Jan 18

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yang, K. J., Shin, S., Piao, L., Shin, E., Li, Y., Kyeong, A. P., Hee, S. B., Won, M., Hong, J., Gi, R. K., Gang, M. H., Jeong, H. S., Chun, T., Brazil, D. P., Hemmings, B. A., & Park, J. (2008). Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding. Journal of Biological Chemistry, 283(3), 1480-1491. https://doi.org/10.1074/jbc.M706361200