title: EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase Cγ, Ca++, and Erk, leading to granule polarization.
abstract: Ewing's sarcoma-associated transcript 2 (EAT-2) is an Src homology 2 domain-containing intracellular adaptor related to signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), the X-linked lymphoproliferative gene product. Both EAT-2 and SAP are expressed in natural killer (NK) cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells. SAP mediates this function by coupling SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target cells. We used a variety of genetic, biochemical, and imaging approaches to define the molecular and cellular mechanisms by which EAT-2 controls NK cell activation. We found that EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by one or two tyrosines located in the carboxyl-terminal tail of EAT-2 but not found in SAP. Unlike SAP, EAT-2 does not enhance conjugate formation. Rather, it accelerates polarization and exocytosis of cytotoxic granules toward hematopoietic target cells. Hence, EAT-2 promotes NK cell activation by molecular and cellular mechanisms distinct from those of SAP. These findings explain the cooperative and essential function of these two adaptors in NK cell activation.
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Luis-Alberto
authors.initials: LA
authors.lastname: Pérez-Quintero
authors.forename: Romain
authors.initials: R
authors.lastname: Roncagalli
authors.forename: Huaijian
authors.initials: H
authors.lastname: Guo
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.forename: Dominique
authors.initials: D
authors.lastname: Davidson
authors.forename: André
authors.initials: A
authors.lastname: Veillette
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004789:Enzyme Activation; D005089:Exocytosis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C103572:SH2D1B protein, human; C499569:Sh2d1a protein, mouse; C491225:Sh2d1b1 protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D014157:Transcription Factors; D014443:Tyrosine; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; D002118:Calcium