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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2421-2428. Prepublished online as a Blood First Edition Paper on January 11, 2008; DOI 10.1182/blood-2007-11-123513. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-11-123513v1 112/6/2421    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gross, O. Articles by Ruland, J. Search for Related Content PubMed PubMed Citation Articles by Gross, O. Articles by Ruland, J. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-B and MAPK activation to selectively control cytokine production Olaf Gross1,*, Christina Grupp1,*, Christian Steinberg2, Stephanie Zimmermann1, Dominikus Strasser1, Nicole Hannesschläger1, Wolfgang Reindl2, Helena Jonsson3, Hairong Huo4, Dan R. Littman4, Christian Peschel1, Wayne M. Yokoyama3, Anne Krug2, and Jürgen Ruland1 1 III Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; 2 II Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; 3 Howard Hughes Medical Institute, Washington University School of Medicine, Rheumatology Division, Department of Medicine, St Louis, MO; and 4 Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine Natural killer (NK) cells are innate immune cells that mediate resistance against viruses and tumors. They express multiple activating receptors that couple to immunoreceptor tyrosine-based activation motif (ITAM)–containing signaling chains for downstream cell activation. Ligation of activating NK-cell receptors induces NK-cell cytotoxicity and cytokine release. How these distinct events are selectively controlled is not well defined. Here we report the identification of a specific signaling pathway that operates downstream of the ITAM-coupled NK-cell receptors NK1.1, Ly49D, Ly49H, and NKG2D. Using primary NK cells from Bcl10–/–, Malt1–/–, Carma1–/–, and Card9–/– mice, we demonstrate a key role for Bcl10 signalosomes in the activation of canonical NF-B signaling as well as JNK and p38 MAPK upon NK-cell triggering. Bcl10 directly cooperates with Malt1 and depends on Carma1 (Card11) but not on Card9 for NK-cell activation. These Bcl10-dependent cascades selectively control cytokine and chemokine production but do not affect NK-cell differentiation or killing. Thus, we identify a molecular basis for the segregation of NK-cell receptor–induced signals for cytokine release and target cell killing and extend the previously recognized roles for CARD-protein/Bcl10/Malt1 complexes in ITAM receptor signaling in innate and adaptive immune cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Hailfinger, G. Lenz, V. Ngo, A. Posvitz-Fejfar, F. Rebeaud, M. Guzzardi, E.-M. M. Penas, J. Dierlamm, W. C. Chan, L. M. Staudt, et al. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma PNAS, November 24, 2009; 106(47): 19946 - 19951. [Abstract] [Full Text] [PDF] M. J. Robinson, F. Osorio, M. Rosas, R. P. Freitas, E. Schweighoffer, O. Gross, J. S. Verbeek, J. Ruland, V. Tybulewicz, G. D. Brown, et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection J. Exp. Med., August 31, 2009; 206(9): 2037 - 2051. [Abstract] [Full Text] [PDF] F. D. Langel, N. A. Jain, J. S. Rossman, L. M. Kingeter, A. K. Kashyap, and B. C. Schaefer Multiple Protein Domains Mediate Interaction between Bcl10 and MALT1 J. Biol. Chem., November 21, 2008; 283(47): 32419 - 32431. [Abstract] [Full Text] [PDF] I. Tassi, M. Cella, R. Presti, A. Colucci, S. Gilfillan, D. R. Littman, and M. Colonna NK cell-activating receptors require PKC-{theta} for sustained signaling, transcriptional activation, and IFN-{gamma} secretion Blood, November 15, 2008; 112(10): 4109 - 4116. [Abstract] [Full Text] [PDF] H. Guo, A. Samarakoon, B. Vanhaesebroeck, and S. Malarkannan The p110{delta} of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation J. Exp. Med., September 29, 2008; 205(10): 2419 - 2435. [Abstract] [Full Text] [PDF]

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