title: Nck-mediated recruitment of BCAP to the BCR regulates the PI(3)K-Akt pathway in B cells.
abstract: The adaptor Nck links receptor signaling to cytoskeleton regulation. Here we found that Nck also controlled the phosphatidylinositol-3-OH kinase (PI(3)K)-kinase Akt pathway by recruiting the adaptor BCAP after activation of B cells. Nck bound directly to the B cell antigen receptor (BCR) via the non-immunoreceptor tyrosine-based activation motif (ITAM) phosphorylated tyrosine residue at position 204 in the tail of the immunoglobulin-α component. Genetic ablation of Nck resulted in defective BCR signaling, which led to hampered survival and proliferation of B cells in vivo. Indeed, antibody responses in Nck-deficient mice were also considerably impaired. Thus, we demonstrate a previously unknown adaptor function for Nck in recruiting BCAP to sites of BCR signaling and thereby modulating the PI(3)K-Akt pathway in B cells.
authors.affiliation: Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, UK.
authors.forename: Angelo
authors.initials: A
authors.lastname: Castello
authors.forename: Mauro
authors.initials: M
authors.lastname: Gaya
authors.forename: Johannes
authors.initials: J
authors.lastname: Tucholski
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.forename: Kun-Hui
authors.initials: KH
authors.lastname: Lu
authors.forename: Anna
authors.initials: A
authors.lastname: Tafuri
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.forename: Facundo D
authors.initials: FD
authors.lastname: Batista
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D007137:Immunoglobulin alpha-Chains / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007137:Immunoglobulin alpha-Chains; C078332:Nck protein; D015513:Oncogene Proteins; C487978:Pik3ap1 protein, mouse; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
references.citation: Cell. 2009 Oct 30;139(3):573-86
references.pmid: 19879843
references.citation: Nat Immunol. 2010 Apr;11(4):303-12
references.pmid: 20228797
references.citation: Annu Rev Immunol. 1994;12:457-86
references.pmid: 8011288
references.citation: EMBO J. 2002 Dec 2;21(23):6461-72
references.pmid: 12456653
references.citation: J Biol Chem. 1998 Aug 14;273(33):20992-5
references.pmid: 9694849
references.citation: Mol Cell Biol. 2002 Apr;22(8):2524-35
references.pmid: 11909947
references.citation: Immunity. 2004 Nov;21(5):681-91
references.pmid: 15539154
references.citation: J Biol Chem. 1991 Aug 15;266(23):14846-9
references.pmid: 1869521
references.citation: J Immunol. 2002 Mar 1;168(5):2127-38
references.pmid: 11859098
references.citation: Cell. 2002 Jun 28;109(7):901-12
references.pmid: 12110186
references.citation: Curr Biol. 2013 Jun 3;23(11):999-1006
references.pmid: 23707428
references.citation: Blood. 2009 Apr 23;113(17):3969-77
references.pmid: 19144984
references.citation: J Exp Med. 2008 Apr 14;205(4):853-68
references.pmid: 18362175
references.citation: Nat Immunol. 2008 Dec;9(12):1388-98
references.pmid: 18978794
references.citation: Curr Biol. 2002 Apr 30;12(9):740-5
references.pmid: 12007418
references.citation: J Immunol. 2007 Jan 15;178(2):740-7
references.pmid: 17202334
references.citation: Eur J Immunol. 2001 Jul;31(7):2126-34
references.pmid: 11449366
references.citation: EMBO J. 2011 Aug 05;30(17):3620-34
references.pmid: 21822214
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7410-4
references.pmid: 1714601
references.citation: Immunol Cell Biol. 1998 Feb;76(1):34-40
references.pmid: 9553774
references.citation: Science. 2006 May 5;312(5774):738-41
references.pmid: 16675699
references.citation: J Exp Med. 2003 Mar 3;197(5):657-67
references.pmid: 12615906
references.citation: J Proteomics. 2012 Feb 2;75(4):1343-56
references.pmid: 22115753
references.citation: Immunity. 1998 Jul;9(1):93-103
references.pmid: 9697839
references.citation: Immunity. 1999 Jan;10(1):117-25
references.pmid: 10023776
references.citation: Cell. 1996 May 31;85(5):639-50
references.pmid: 8646773
references.citation: Immunity. 2007 Jul;27(1):160-71
references.pmid: 17658276
references.citation: J Biol Chem. 1998 Sep 25;273(39):25171-8
references.pmid: 9737977
references.citation: Blood. 2004 Aug 1;104(3):784-7
references.pmid: 15069012
references.citation: Immunity. 2006 Oct;25(4):545-57
references.pmid: 17000121
references.citation: Blood. 2008 Feb 1;111(3):1497-503
references.pmid: 18025150
references.citation: Nat Immunol. 2005 Jan;6(1):80-9
references.pmid: 15558067
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15529-34
references.pmid: 20709959
references.citation: J Immunol. 2010 Dec 15;185(12):7518-26
references.pmid: 21078909
references.citation: J Biol Chem. 1992 Apr 25;267(12):8613-9
references.pmid: 1569106
references.citation: J Exp Med. 2002 Mar 4;195(5):535-45
references.pmid: 11877477
references.citation: EMBO J. 1994 Mar 15;13(6):1341-9
references.pmid: 8137818
references.citation: Immunity. 2006 Jul;25(1):55-65
references.pmid: 16860757
references.citation: Immunity. 2004 May;20(5):589-99
references.pmid: 15142527
references.citation: Nature. 2006 Apr 6;440(7085):818-23
references.pmid: 16525419
references.citation: J Exp Med. 1991 May 1;173(5):1213-25
references.pmid: 1827140
references.citation: Immunity. 2000 Dec;13(6):817-27
references.pmid: 11163197
references.citation: J Biol Chem. 2006 Jun 30;281(26):18236-45
references.pmid: 16636066
references.citation: Mol Cell Biol. 1995 Oct;15(10):5725-31
references.pmid: 7565724
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13789-94
references.pmid: 16940357
references.citation: EMBO J. 2007 Feb 21;26(4):1140-9
references.pmid: 17290227
references.citation: Mol Cell Biol. 2003 Jul;23(13):4586-97
references.pmid: 12808099
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8345-50
references.pmid: 18550831