Apoptosis or programmed cell death plays an essential role during developme
nt 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 ch
aracteristic features that occur following activation of caspases, a collec
tive 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 atten
tion both as an outcome of FasR activation and as a factor regulating FasR
responses. Tyrosine-directed phosphorylation has been implicated to be indu
ced 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 mechani
sms. Furthermore, phosphorylation-based signaling serves as a potent modifi
er 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 synthesi
zed proteins. Signaling through phosphorylation also regulates the expressi
on of the Fas Ligand (FasL), the FasR, as well as various other proteins th
at affect the outcome of receptor stimulation. While the involvement of pho
sphorylation has been established in FasR responses, the targets, molecular
mechanisms, and biological significance of this aspect of the FasR signali
ng machinery still require further elucidation.