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Blood, 1 December 2007, Vol. 110, No. 12, pp. 3968-3977. Prepublished online as a Blood First Edition Paper on August 21, 2007; DOI 10.1182/blood-2007-01-071167. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-01-071167v1 110/12/3968    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 Brenner, D. Articles by Arnold, R. Search for Related Content PubMed PubMed Citation Articles by Brenner, D. Articles by Arnold, R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 31, 2007 Accepted August 13, 2007 Caspase cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes Dirk Brenner, Alexander Golks, Mareike Becker, Wolfgang Muller, Christian R Frey, Rostislav Novak, Doron Melamed, Friedemann Kiefer, Peter H Krammer, and Rudiger Arnold* Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Immunology, Faculty of Medicine, Technion, Haifa, Israel Vascular Cell Biology, Max-Planck-Institute for Molecular Biomedicine, Munster, Germany * Corresponding author; email: r.arnold{at}dkfz.de. Life and death of peripheral lymphocytes is strictly controlled to maintain physiological levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and is depends partially on the CD95/CD95L system. Recently, we have shown that hematopoetic progenitor kinase 1 (HPK1) determines T cell fate. While full length HPK1 is essential for NF-B activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-B and sensitize towards AICD by a yet undefined cell death pathway. Here we show that upon IL-2 driven expansion of primary T cells HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-B-dependent anti-apoptotic Bcl-2 family members, but not of the pro-apoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system, but involving caspase-9. Knock-down of HPK1/HPK1-C or Bim by siRNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of anti-apoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Brenner, M. Brechmann, S. Rohling, M. Tapernoux, T. Mock, D. Winter, W. D. Lehmann, F. Kiefer, M. Thome, P. H. Krammer, et al. Phosphorylation of CARMA1 by HPK1 is critical for NF-{kappa}B activation in T cells PNAS, August 25, 2009; 106(34): 14508 - 14513. [Abstract] [Full Text] [PDF] S. Alzabin, N. Bhardwaj, F. Kiefer, S. Sawasdikosol, and S. Burakoff Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation J. Immunol., May 15, 2009; 182(10): 6187 - 6194. [Abstract] [Full Text] [PDF]

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