FADD/MORT1, a signal transducer that can promote cell death or cell growth

Abstract

FADD/MORT1 is a cytosolic adaptor protein which is critical for signalling from CD95 (Fas/APO-1) and certain other members of the tumour necrosis factor receptor (TNF-R) family (called 'death receptors'). Two protein interaction domains have been identified in FADD/MORT1. The C-terminal 'death domain' is needed for recruitment of FADD/MORT1 to ligated 'death receptors' and the N-terminal 'death effector domain' mediates oligomerisation and activation of caspase-8 zymogens. Caspase-8 activates other cysteine proteases by cleavage and this starts a proteolytic cascade which constitutes the 'point of no return' in apoptosis signalling. Experiments in mice lacking FADD/MORT1 function proved that this adaptor is required for CD95- and TNF-RI-transduced cell death but is dispensable for other pathways to apoptosis. Surprisingly, FADD/MORT1 is also essential for mitogen-induced proliferation of T-lymphocytes. Therapeutic activation of FADD/MORT1 function may be used to kill unwanted cells in cancer or autoimmunity and its suppression may help prevent cell death in certain degenerative disorders.