title: Ras-related C3 Botulinum Toxin Substrate (Rac) and Src Family Kinases (SFK) Are Proximal and Essential for Phosphatidylinositol 3-Kinase (PI3K) Activation in Natural Killer (NK) Cell-mediated Direct Cytotoxicity against Cryptococcus neoformans.
abstract: The activity of Rac in leukocytes is essential for immunity. However, its role in NK cell-mediated anti-microbial signaling remains unclear. In this study, we investigated the role of Rac in NK cell mediated anti-cryptococcal killing. We found thatCryptococcus neoformansindependently activates both Rac and SFK pathways in NK cells, and unlike in tumor killing,Cryptococcusinitiated a novel Rac → PI3K → Erk cytotoxicity cascade. Remarkably, Rac was not required for conjugate formation, despite its essential role in NK cytotoxicity againstC. neoformans Taken together, our data show that, unlike observations with tumor cells, NK cells use a novel Rac cytotoxicity pathway in conjunction with SFK, to killC. neoformans.
authors: From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Richard F
authors: RF
authors: Xiang
authors: From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Danuta
authors: D
authors: Stack
authors: From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Shaunna M
authors: SM
authors: Huston
authors: From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Shu Shun
authors: SS
authors: Li
authors: From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Henry
authors: H
authors: Ogbomo
authors: From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Stephen K
authors: SK
authors: Kyei
authors: From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada Internal Medicine and cmody@ucalgary.ca.
authors: Christopher H
authors: CH
authors: Mody
mesh_terms: D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D011753:Pyrones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011753:Pyrones; D011804:Quinolines; D034741:RNA, Small Interfering; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D019061:src-Family Kinases; D000097766:RAC2 GTP-Binding Protein; C506907:EHT 1864; C107953:RAC1 protein, human; C535150:MAPK1 protein, human
keywords: Cellular signaling; Cryptococcus; Rac (Rac GTPase); Src; adhesion; fungi; natural killer cells (NK cells); phosphatidylinositide 3-kinase (PI 3-kinase)