title: Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells.
abstract: Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma and various autoimmune disorders. Here we identified a signaling pathway that was exclusively responsible for the production of inflammatory cytokines but not for cytotoxicity. Recognition of tumor cells expressing the NK cell-activatory ligands H60 or CD137L by mouse natural killer (NK) cells led to efficient cytotoxicity and the production of inflammatory cytokines. Both of those effector functions required the kinases Lck, Fyn and PI(3)K (subunits p85α and p110δ) and the signaling protein PLC-γ2. However, a complex of Fyn and the adaptor ADAP exclusively regulated the production of inflammatory cytokines but not cytotoxicity in NK cells. That unique function of ADAP required a Carma1-Bcl-10-MAP3K7 signaling axis. Our results have identified molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.
authors.affiliation: Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Milwaukee, Wisconsin, USA.
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Rajasekaran
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Schuldt
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Peterson
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Vishva
authors.initials: V
authors.lastname: Dixit
authors.forename: Monica S
authors.initials: MS
authors.lastname: Thakar
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Malarkannan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D051076:Proto-Oncogene Proteins c-fyn; D000099151:MAP Kinase Kinase Kinase 7; C488088:Bcl10 protein, mouse; C496467:Card11 protein, mouse; C491468:Fyb protein, mouse; C494960:Fyn protein, mouse
references.citation: Science. 1999 Jul 30;285(5428):730-2
references.pmid: 10426994
references.citation: J Biol Chem. 1994 Jan 21;269(3):1927-33
references.pmid: 8294442
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7366-70
references.pmid: 8394019
references.citation: J Biol Chem. 1997 Sep 5;272(36):22771-5
references.pmid: 9278437
references.citation: J Exp Med. 2008 Jul 7;205(7):1611-9
references.pmid: 18573910
references.citation: Immunity. 2012 Jun 29;36(6):974-85
references.pmid: 22683124
references.citation: J Exp Med. 2001 Jun 18;193(12):1413-24
references.pmid: 11413196
references.citation: Am J Respir Cell Mol Biol. 2001 Apr;24(4):469-74
references.pmid: 11306441
references.citation: J Exp Med. 1996 Dec 1;184(6):2119-28
references.pmid: 8976168
references.citation: Curr Biol. 2003 Jul 15;13(14):1252-8
references.pmid: 12867038
references.citation: J Immunol. 1993 Aug 1;151(3):1255-62
references.pmid: 8335927
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8779-84
references.pmid: 9671755
references.citation: Nat Immunol. 2003 Jun;4(6):557-64
references.pmid: 12740575
references.citation: J Immunol. 2006 Oct 15;177(8):5365-76
references.pmid: 17015722
references.citation: Eur J Immunol. 1991 Mar;21(3):843-6
references.pmid: 1826268
references.citation: Science. 2005 Apr 1;308(5718):114-8
references.pmid: 15802604
references.citation: Science. 2007 May 4;316(5825):754-8
references.pmid: 17478723
references.citation: Nat Immunol. 2005 Nov;6(11):1087-95
references.pmid: 16186825
references.citation: Blood. 2007 Nov 1;110(9):3202-8
references.pmid: 17644738
references.citation: Blood. 2013 Apr 18;121(16):3135-46
references.pmid: 23407547
references.citation: Immunity. 2000 Sep;13(3):333-44
references.pmid: 11021531
references.citation: Nat Immunol. 2002 Sep;3(9):836-43
references.pmid: 12154360
references.citation: Int Immunol. 2006 Aug;18(8):1305-14
references.pmid: 16775024
references.citation: Nat Immunol. 2003 Jun;4(6):565-72
references.pmid: 12740576
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3017-22
references.pmid: 18287025
references.citation: J Biol Chem. 2010 Apr 9;285(15):11100-5
references.pmid: 20164171
references.citation: J Immunol. 2002 Oct 15;169(8):4230-6
references.pmid: 12370353
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6329-34
references.pmid: 17395718
references.citation: Biochem Biophys Res Commun. 1996 Mar 27;220(3):729-34
references.pmid: 8607833
references.citation: Cell Immunol. 1996 Jan 10;167(1):63-71
references.pmid: 8548846
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4330-5
references.pmid: 9113989
references.citation: J Exp Med. 1994 Jun 1;179(6):1799-808
references.pmid: 7515100
references.citation: J Immunol. 2006 Jun 1;176(11):6615-23
references.pmid: 16709819
references.citation: J Exp Med. 2008 Sep 29;205(10):2419-35
references.pmid: 18809712
references.citation: J Exp Med. 1998 Jan 5;187(1):123-8
references.pmid: 9419218
references.citation: J Biol Chem. 2008 Sep 26;283(39):26409-22
references.pmid: 18660530
references.citation: J Immunol. 2000 Dec 1;165(11):6193-204
references.pmid: 11086053
references.citation: Nat Cell Biol. 2002 Aug;4(8):556-64
references.pmid: 12134156
references.citation: J Immunol. 2006 Oct 15;177(8):5122-8
references.pmid: 17015696
references.citation: J Immunol. 2008 Jun 15;180(12):8093-101
references.pmid: 18523273
references.citation: Immunity. 2007 Jan;26(1):55-66
references.pmid: 17189706
references.citation: Curr Biol. 2003 Jul 15;13(14):1247-51
references.pmid: 12867037
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21143-8
references.pmid: 19955438
references.citation: Science. 2001 Sep 21;293(5538):2263-5
references.pmid: 11567141
references.citation: Blood. 2010 Apr 15;115(15):3058-69
references.pmid: 20008791
references.citation: Blood. 2005 Jan 1;105(1):233-40
references.pmid: 15328154
references.citation: J Exp Med. 2003 May 5;197(9):1221-7
references.pmid: 12732664
references.citation: J Biol Chem. 2011 Sep 9;286(36):31213-24
references.pmid: 21771792
references.citation: J Exp Med. 2000 Oct 2;192(7):1059-68
references.pmid: 11015446
references.citation: Trends Immunol. 2005 Aug;26(8):440-6
references.pmid: 15979409