title: The membrane adaptor LAT is proteolytically cleaved following Fas engagement in a tyrosine phosphorylation-dependent fashion.
abstract: Engagement of the TCR (T-cell receptor) induces tyrosine phosphorylation of the LAT (linker for the activation of T-cells) adaptor, and thereby it recruits several cytosolic mediators for downstream signalling pathways. The Fas protein is essential for T-lymphocyte apoptosis, and following Fas engagement, many proteins are proteolytically cleaved, including several molecules that are important for the transduction of TCR intracellular signals. In the present study, we demonstrate that the adaptor LAT is also subject to a proteolytic cleavage in mature T-lymphocytes and thymocytes in response to Fas engagement, and also on TCR stimulation, and we identify three aspartic acid residues at which LAT is cleaved. Interestingly, these aspartic acid residues are located in proximity to several functionally important tyrosine residues of LAT, raising the possibility that their phosphorylation could modulate LAT cleavage. Consistent with that hypothesis, we show that induction of phosphorylation by pervanadate or H2O2 in Jurkat cells and thymocytes inhibits Fas-mediated cleavage of LAT. Moreover, we show that LAT proteolysis is also enhanced during anergy induction of primary human T-cells, suggesting that LAT cleavage may act as a regulator of TCR-mediated activation of T-cells and not only as a transducer of cell death promoting stimuli.
authors.affiliation: Core Research Facility for Health Sciences, Department of Biomedicine, Biotechnology and Public Health (Immunology), University of C´adiz, c/ Dr Mara˜non, n◦ 3, C´adiz 1102, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: García-Blesa
authors.forename: Mikolaj
authors.initials: M
authors.lastname: Klossowicz
authors.forename: Carmen
authors.initials: C
authors.lastname: López-Osuna
authors.forename: Mario
authors.initials: M
authors.lastname: Martínez-Florensa
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: García-Cózar
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Miazek
authors.forename: Enrique
authors.initials: E
authors.lastname: Aguado
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D059748:Proteolysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491901:FAS protein, human; C110810:LAT protein, human; D008565:Membrane Proteins; D019014:fas Receptor; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases