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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2345-2352. Prepublished online as a Blood First Edition Paper on June 8, 2004; DOI 10.1182/blood-2003-12-4260. This Article Full Text (PDF) All Versions of this Article: 2003-12-4260v1 104/8/2345    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yamazaki, T. Articles by Sato, Y. Search for Related Content PubMed PubMed Citation Articles by Yamazaki, T. Articles by Sato, Y. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 15, 2003 Accepted May 25, 2004 Puromycin insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyses PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell proliferation and angiogenesis Tohru Yamazaki, Tetsuya Akada, Osamu Niizeki, Takahiro Suzuki, Hiroki Miyashita, and Yasufumi Sato* Department of Vascular Biology, IDAC, Tohoku University, Sendai, Miyagi, Japan * Corresponding author; email: y-sato{at}idac.tohoku.ac.jp. Puromycin insensitive leucyl-specific aminopeptidase (PILSAP) plays an important role in angiogenesis by regulating the proliferation and migration of endothelial cells (ECs). Here we characterize the mechanism by which PILSAP regulates the VEGF-stimulated proliferation of ECs. The specific elimination of PILSAP expression or its enzymatic activity inhibited VEGF-stimulated G1/S transition in ECs. This G1 arrest correlated with reduced CDK4/6 activity and Rb protein phosphorylation. Analyses of signaling molecules upstream of CDK4/6 revealed that S6K activation was affected by PILSAP, whereas that of PI3K, Akt and ERK1/2 was not. We further demonstrated that PILSAP bound PDK1 and removed 9 amino acids from its N-terminus, which allowed S6K to associate with PDK1 and PILSAP upon VEGF stimulation. We constructed mutant PILSAP, which lacked the aminopeptidase activity but bound PDK1. Mutant PILSAP abrogated S6K activation upon VEGF stimulation in a dominant negative manner. An N-terminal truncated form of PDK1 abolished the dominant negative effect of mutant PILSAP. Finally, the introduction of a mutated PILSAP gene in ECs inhibited angiogenesis and retarded tumor growth in vivo. These results indicate that PILSAP plays a crucial role in the cell cycle progression of ECs and angiogenesis via the binding and modification of PDK1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Abe and Y. Sato Puromycin insensitive leucyl-specific aminopeptidase (PILSAP) is required for the development of vascular as well as hematopoietic system in embryoid bodies. Genes Cells, July 1, 2006; 11(7): 719 - 729. [Abstract] [Full Text] [PDF] A. Islam, B. Adamik, F. I. Hawari, G. Ma, F. N. Rouhani, J. Zhang, and S. J. Levine Extracellular TNFR1 Release Requires the Calcium-dependent Formation of a Nucleobindin 2-ARTS-1 Complex J. Biol. Chem., March 10, 2006; 281(10): 6860 - 6873. [Abstract] [Full Text] [PDF]

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