Phosphorylation-Based signaling in Fas receptor-mediated apoptosis.
Apoptosis or programmed cell death plays an essential role during development of the immune system, in immune responses, and in the control of tissue homeostasis in the adult. An important physiological mediator of apoptosis is the Fas/APO-1/CD95 receptor (FasR), a surface receptor belonging to the tumor necrosis factor receptor family. Apoptosis consists of a series of characteristic features that occur following activation of caspases, a collective term for apoptosis-specific proteases. The focus in FasR research has been on determining the mechanisms resulting in caspase activation. However, the role of phosphorylation-based signaling has received increasing attention both as an outcome of FasR activation and as a factor regulating FasR responses. Tyrosine-directed phosphorylation has been implicated to be induced and required during FasR stimulation. The FasR also activates all major signaling pathways that belong to the family of mitogen-activated protein kinase (MAPK) pathways, by either caspase-independent or -dependent mechanisms. Furthermore, phosphorylation-based signaling serves as a potent modifier of FasR responses. In this respect, especially the extracellular signal-regulated kinase and the phosphoinositide 3-kinase signaling pathways have been established as important regulators. This type of control seems to be directly phosphorylation-mediated without the requirement of newly synthesized proteins. Signaling through phosphorylation also regulates the expression of the Fas ligand (FasL), the FasR, as well as various other proteins that affect the outcome of receptor stimulation. While the involvement of phosphorylation has been established in FasR responses, the targets, molecular mechanisms, and biological significance of this aspect of the FasR signaling machinery still require further elucidation.
Holmström
T H
TH
Turku Centre for Biotechnology, University of Turku, Finland.
Eriksson
J E
JE
D017209:Apoptosis; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014443:Tyrosine; D019014:fas Receptor / Q000378:metabolism*
D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D014443:Tyrosine