HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 32, 33759-33767, August 6, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/32/33759    most recent M402055200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sato, S. Articles by Tsuruo, T. Search for Related Content PubMed PubMed Citation Articles by Sato, S. Articles by Tsuruo, T. Social Bookmarking                      What's this?

Involvement of 3-Phosphoinositide-dependent Protein Kinase-1 in the MEK/MAPK Signal Transduction Pathway^*

Saori Sato, Naoya Fujita, and Takashi Tsuruo¶

From the Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan and Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan

The phosphatidylinositide-3-OH kinase/3-phospho-inositide-dependent protein kinase-1 (PDK1)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles in the regulation of cell survival and proliferation. Despite their importance, however, the cross-talk between these two pathways has not been fully understood. Here we report that PDK1 promotes MAPK activation in a MEK-dependent manner. In vitro kinase assay revealed that the direct targets of PDK1 in the MAPK pathway were the upstream MAPK kinases MEK1 and MEK2. The identified PDK1 phosphorylation sites in MEK1 and MEK2 are Ser²²² and Ser²²⁶, respectively, and are known to be essential for full activation. To date, these sites are thought to be phosphorylated by Raf kinases. However, PDK1 gene silencing using small interference RNA demonstrates that PDK1 is associated with maintaining the steady-state phosphorylated MEK level and cell growth. The small interference RNA-mediated down-regulation of PDK1 attenuated maximum MEK and MAPK activities but could not prolong MAPK signaling duration. Stable and transient expression of constitutively active MEK1 overcame these effects. Our results suggest a novel cross-talk between the phosphatidylinositide-3-OH kinase/PDK1/Akt pathway and the Raf/MEK/MAPK pathway.

Received for publication, February 25, 2004 , and in revised form, June 1, 2004.

^* This work was supported in part by a special grant for Advanced Research on Cancer from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to T. T.) and by a grant for Research Fellowships of the Japanese Society for the Promotion of Science for Young Scientists (to S. S.). 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.

^¶ To whom correspondence should be addressed. Tel.: 81-3-5841-7861; Fax: 81-3-5841-8487; E-mail: ttsuruo{at}iam.u-tokyo.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. W. Bradley, M. M. Ruan, and M. J. Oursler Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK Pathway J. Biol. Chem., March 21, 2008; 283(12): 8055 - 8064. [Abstract] [Full Text] [PDF]

				G. M. Fuhler, A. L. Drayer, S. G. M. Olthof, J. J. Schuringa, P. J. Coffer, and E. Vellenga Reduced activation of protein kinase B, Rac, and F-actin polymerization contributes to an impairment of stromal cell derived factor-1 induced migration of CD34+ cells from patients with myelodysplasia Blood, January 1, 2008; 111(1): 359 - 368. [Abstract] [Full Text] [PDF]

				X. Leleu, X. Jia, J. Runnels, H. T. Ngo, A.-S. Moreau, M. Farag, J. A. Spencer, C. M. Pitsillides, E. Hatjiharissi, A. Roccaro, et al. The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia Blood, December 15, 2007; 110(13): 4417 - 4426. [Abstract] [Full Text] [PDF]

				N. Ghosh-Choudhury, C. C. Mandal, and G. G. Choudhury Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation J. Biol. Chem., February 16, 2007; 282(7): 4983 - 4993. [Abstract] [Full Text] [PDF]

				J. Mookerjee Basu, A. Mookerjee, P. Sen, S. Bhaumik, P. Sen, S. Banerjee, K. Naskar, S. K. Choudhuri, B. Saha, S. Raha, et al. Sodium Antimony Gluconate Induces Generation of Reactive Oxygen Species and Nitric Oxide via Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Activation in Leishmania donovani-Infected Macrophages. Antimicrob. Agents Chemother., May 1, 2006; 50(5): 1788 - 1797. [Abstract] [Full Text] [PDF]

				H. He, H.-T. Cho, W. Li, T. Kawakita, L. Jong, and S. C. G. Tseng Signaling-Transduction Pathways Required for Ex Vivo Expansion of Human Limbal Explants on Intact Amniotic Membrane Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 151 - 157. [Abstract] [Full Text] [PDF]

				H. Tanaka, N. Fujita, and T. Tsuruo 3-Phosphoinositide-dependent Protein Kinase-1-mediated I{kappa}B Kinase {beta} (IKKB) Phosphorylation Activates NF-{kappa}B Signaling J. Biol. Chem., December 9, 2005; 280(49): 40965 - 40973. [Abstract] [Full Text] [PDF]

				R. A. Mesa, D. Loegering, H. L. Powell, K. Flatten, S. J. H. Arlander, N. T. Dai, M. P. Heldebrant, B. T. Vroman, B. D. Smith, J. E. Karp, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine Blood, July 1, 2005; 106(1): 318 - 327. [Abstract] [Full Text] [PDF]

				K. Flatten, N. T. Dai, B. T. Vroman, D. Loegering, C. Erlichman, L. M. Karnitz, and S. H. Kaufmann The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons J. Biol. Chem., April 8, 2005; 280(14): 14349 - 14355. [Abstract] [Full Text] [PDF]

				Y. Dai, M. Rahmani, X.-Y. Pei, P. Khanna, S. I. Han, C. Mitchell, P. Dent, and S. Grant Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK Blood, February 15, 2005; 105(4): 1706 - 1716. [Abstract] [Full Text] [PDF]