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Title: Non-T cell activation linker (NTAL) proteolytic cleavage as a terminator of activatory intracellular signals.
Authors: Arbulo-Echevarria, Mikel M
Muñoz-Miranda, Juan Pedro
Caballero-García, Andrés
Poveda-Díaz, José L
Fernández-Ponce, Cecilia
Durán-Ruiz, M Carmen
Miazek, Arkadiusz
García-Cózar, Francisco
Aguado, Enrique
Keywords: B lymphocytes;LAT2;caspases;monocytes;signal transduction
metadata.dc.subject.mesh: Adaptor Proteins, Signal Transducing
Caspase 3
Caspase 8
Cells, Cultured
Fas Ligand Protein
Jurkat Cells
Lymphocyte Activation
Signal Transduction
fas Receptor
Issue Date: 1-Feb-2016
Abstract: Non-T cell activation linker is an adaptor protein that is tyrosine phosphorylated upon cross-linking of immune receptors expressed on B lymphocytes, NK cells, macrophages, basophils, or mast cells, allowing the recruitment of cytosolic mediators for downstream signaling pathways. Fas receptor acts mainly as a death receptor, and when cross-linked with Fas ligand, many proteins are proteolytically cleaved, including several signaling molecules in T and B cells. Fas receptor triggering also interferes with TCR intracellular signals, probably by means of proteolytic cleavage of several adaptor proteins. We have previously found that the adaptor linker for activation of T cells, evolutionarily related to non-T cell activation linker, is cleaved upon proapoptotic stimuli in T lymphocytes and thymocytes, in a tyrosine phosphorylation-dependent fashion. Here, we describe non-T cell activation linker proteolytic cleavage triggered in human B cells and monocytes by Fas cross-linking and staurosporine treatment. Non-T cell activation linker is cleaved, producing an N-terminal fragment of ∼22 kDa, and such cleavage is abrogated in the presence of caspase 8/granzyme B and caspase 3 inhibitors. Moreover, we have identified an aspartic acid residue at which non-T cell activation linker is cleaved, which similar to linker for activation of T cells, this aspartic acid residue is located close to tyrosine and serine residues, suggesting an interdependence of phosphorylation and proteolytic cleavage. Consistently, induction of non-T cell activation linker phosphorylation by pervanadate inhibits its cleavage. Interestingly, the truncated isoform of non-T cell activation linker, generated after cleavage, has a decreased signaling ability when compared with the full-length molecule. Altogether, our results suggest that cleavage of transmembrane adaptors constitutes a general mechanism for signal termination of immune receptors.
metadata.dc.identifier.doi: 10.1189/jlb.2A0715-318R
Appears in Collections:Producción 2020

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