biostudies-literatureMay RMNIAID NIH HHSNHLBI NIH HHSNCI NIH HHSNIAMS NIH HHS3135-46https://www.ebi.ac.uk/biostudies/studies/S-EPMC3630829biostudies-literatureUnknown121(16)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-BloodMurine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function.PMC3630829L40 AI084669R01 HL107589R21 AI073409K08HL086503T32AR007442R21AI073409R01HL111501T32 AR007442K08 HL086503R01AI067946R01 AI067946R01 HL111501R01 HL089745R01HL089745K08 CA166184R01HL107589May RMOkumura MPhilip NHYang EZhang WKambayashi TRak GBassiri HOrange JSMace EMHsu CJBaumgart TNichols KEfalseMurine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function.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-2013-01-01T00:00:00Z2013 Apr2025-04-25T22:08:43.483Z2019-03-27T01:07:40ZS-EPMC36308292340754710.1182/blood-2012-12-474361