Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells.

Abstract	Signaling lymphocytic activation molecule F7 (SLAMF7) is a receptor present on immune cells, including natural killer (NK) cells. It is also expressed on multiple myeloma (MM) cells. This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express or do not express the adaptor EAT-2. Since MM cells lack EAT-2, we elucidated the inhibitory effectors of SLAMF7 in EAT-2-negative NK cells and tested whether these effectors were triggered in MM cells. SLAMF7-mediated inhibition in NK cells lacking EAT-2 was mediated by SH2 domain-containing inositol phosphatase 1 (SHIP-1), which was recruited via tyrosine 261 of SLAMF7. Coupling of SLAMF7 to SHIP-1 required Src kinases, which phosphorylated SLAMF7. Although MM cells lack EAT-2, elotuzumab did not induce inhibitory signals in these cells. This was at least partly due to a lack of CD45, a phosphatase required for Src kinase activation. A defect in SLAMF7 function was also observed in CD45-deficient NK cells. Hence, SLAMF7-triggered inhibition is mediated by a mechanism involving Src kinases, CD45, and SHIP-1 that is defective in MM cells. This defect might explain why elotuzumab eliminates MM cells by an indirect mechanism involving the activation of NK cells.
Authors	Huaijian Guo, Mario-Ernesto Cruz-Munoz, Ning Wu, Michael Robbins, André Veillette
Journal	Molecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 1 Pg. 41-51 (Jan 2015) ISSN: 1098-5549 [Electronic] United States
PMID	25312647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Chemical References	Antibodies, Monoclonal, Humanized Receptors, Immunologic SLAMF7 protein, human Signaling Lymphocytic Activation Molecule Family elotuzumab Tyrosine src-Family Kinases Phosphoric Monoester Hydrolases Leukocyte Common Antigens PTPRC protein, human Inositol Polyphosphate 5-Phosphatases INPP5D protein, human Inpp5d protein, mouse Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Topics	Animals Antibodies, Monoclonal, Humanized (pharmacology) COS Cells Chlorocebus aethiops Gene Expression Regulation, Neoplastic HeLa Cells Humans Inositol Polyphosphate 5-Phosphatases Killer Cells, Natural (cytology) Leukocyte Common Antigens (metabolism) Melanoma, Experimental Mice Mice, Inbred C57BL Multiple Myeloma (metabolism) Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases Phosphoric Monoester Hydrolases (metabolism) Phosphorylation Protein Structure, Tertiary RNA Interference Receptors, Immunologic (metabolism) Signal Transduction Signaling Lymphocytic Activation Molecule Family Tyrosine (chemistry) src-Family Kinases (metabolism)

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