Rap1b facilitates NK cell functions via IQGAP1-mediated signalosomes.
Rap1 GTPases control immune synapse formation and signaling in lymphocytes. However, the precise molecular mechanism by which Rap1 regulates natural killer (NK) cell activation is not known. Using Rap1a or Rap1b knockout mice, we identify Rap1b as the major isoform in NK cells. Its absence significantly impaired LFA1 polarization, spreading, and microtubule organizing center (MTOC) formation in NK cells. Neither Rap1 isoform was essential for NK cytotoxicity. However, absence of Rap1b impaired NKG2D, Ly49D, and NCR1-mediated cytokine and chemokine production. Upon activation, Rap1b colocalized with the scaffolding protein IQGAP1. This interaction facilitated sequential phosphorylation of B-Raf, C-Raf, and ERK1/2 and helped IQGAP1 to form a large signalosome in the perinuclear region. These results reveal a previously unrecognized role for Rap1b in NK cell signaling and effector functions.
Awasthi
Aradhana
A
Molecular Immunology, Blood Research Institute, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Samarakoon
Asanga
A
Chu
Haiyan
H
Kamalakannan
Rajasekaran
R
Quilliam
Lawrence A
LA
Chrzanowska-Wodnicka
Magdalena
M
White
Gilbert C
GC
Malarkannan
Subramaniam
S
D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D015398:Signal Transduction; D020668:rap GTP-Binding Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000276:immunology* / Q000378:metabolism
C101203:IQ motif containing GTPase activating protein 1; C527086:Klrk1 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020703:ras GTPase-Activating Proteins; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins