title: Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function.
abstract: Signaling pathways leading to natural killer (NK)-cell effector function are complex and incompletely understood. Here, we investigated the proximal signaling pathways downstream of the immunotyrosine-based activation motif (ITAM) bearing activating receptors. We found that the adaptor molecule SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is recruited to microclusters at the plasma membrane in activated NK cells and that this is required for initiation of downstream signaling and multiple NK-cell effector functions in vitro and in vivo. Surprisingly, we found that 2 types of proximal signaling complexes involving SLP-76 were formed. In addition to the canonical membrane complex formed between SLP-76 and linker for activation of T cells (LAT) family members, a novel LAT family-independent SLP-76-dependent signaling pathway was identified. The LAT family-independent pathway involved the SH2 domain of SLP-76 and adhesion and degranulation-promoting adaptor protein (ADAP). Both the LAT family-dependent and ADAP-dependent pathway contributed to interferon-gamma production and cytotoxicity; however, they were not essential for other SLP-76-dependent events, including phosphorylation of AKT and extracellular signal-related kinase and cellular proliferation. These results demonstrate that NK cells possess an unexpected bifurcation of proximal ITAM-mediated signaling, each involving SLP-76 and contributing to optimal NK-cell function.
authors: Division of Transfusion Medicine and Therapeutic Pathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors: Rebecca M
authors: RM
authors: May
authors: Mariko
authors: M
authors: Okumura
authors: Chin-Jung
authors: CJ
authors: Hsu
authors: Hamid
authors: H
authors: Bassiri
authors: Enjun
authors: E
authors: Yang
authors: Gregory
authors: G
authors: Rak
authors: Emily M
authors: EM
authors: Mace
authors: Naomi H
authors: NH
authors: Philip
authors: Weiguo
authors: W
authors: Zhang
authors: Tobias
authors: T
authors: Baumgart
authors: Jordan S
authors: JS
authors: Orange
authors: Kim E
authors: KE
authors: Nichols
authors: Taku
authors: T
authors: Kambayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D027182:Amino Acid Transport System y+ / Q000276:immunology*; D027241:Amino Acid Transport System y+L; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D027301:Fusion Regulatory Protein 1, Light Chains / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000276:immunology*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D027301:Fusion Regulatory Protein 1, Light Chains; C491468:Fyb protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D010750:Phosphoproteins; C518286:SLC7A8 protein, mouse; C092947:SLP-76 signal Transducing adaptor proteins; C518287:Slc7a7 protein, mouse; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt