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

https://doi.org/10.1016/S1357-2725(99)00003-5Get rights and content

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.

Introduction

Members of the TNF-R family of receptors have pleiotropic activities in mammalian cells. The same receptor can trigger cell proliferation, cell differentiation or cell death depending on the responding cell type and/or its metabolic state (reviewed by Ref.[1]). For example, CD95 plays an essential role in removing chronically activated lymphocytes by apoptotic cell death, but has also been reported to transmit a costimulatory signal in antigen-stimulated quiescent T-cells. Further, TNF-RI plays a critical role in liver regeneration following partial hepatectomy, yet transmits a death signal in many types of cultured tumour cells (reviewed by[1]). A protein–protein interaction motif, called a `death domain', is present in the intracellular portion of several TNF-R family members (e.g. CD95, TNF-RI, DR3) and is essential for apoptosis signalling by these receptors (reviewed by Ref.[1]).

Section snippets

Structure

The human and mouse FADD/MORT1 genes were cloned from cDNA expression libraries derived from HeLa cells, human B lymphocytes or mouse T-lymphocytes, in yeast-two-hybrid screens designed to identify proteins that interact with the cytoplasmic region of CD952, 3, 4. FADD/MORT1 binds only to wild-type CD95 but not to signalling-deficient mutants of this receptor, consistent with the notion that it is a critical signal transducer.

The human FADD/MORT1 gene is composed of two exons (286 and 341 base

Expression, subcellular localisation and posttranslational modification

Northern blot and in situ hybridisation analyses showed that FADD/MORT1 mRNA is expressed at relatively high levels in essentially all adult and embryonic tissues in both mice and humans3, 13. In untreated cells FADD/MORT1 protein localises to the cytosol, but upon CD95 ligation it is rapidly recruited to the plasma membrane where it forms an integral part of the CD95 `death inducing signalling complex' (DISC)[14]. A substantial fraction of FADD/MORT1 molecules is phosphorylated by a presently

Biological function

The biological function of FADD/MORT1 was investigated in experiments with cultured cell lines or transgenic mice expressing a dominant-interfering mutant of this protein[15]and in FADD/MORT1-deficient mice generated by targeted disruption of the corresponding gene13, 16. A dominant-interfering mutant of FADD/MORT1 was produced by deletion of the NH2-terminal `death effector domain' (Fig. 1b and Fig. 2 grey boxes). This truncated protein, here referred to as FADD-DN, competes with wild-type

Possible medical applications

Abnormalities in the regulation of apoptosis are implicated as a cause or contributing factor in many diseases. The protracted survival of cells that are normally doomed (e.g. activated lymphocytes) can be an early event in tumourigenesis[19]or lead to autoimmune disease[20]. Conversely, premature death of cells that are normally long-lived, such as for instance neurons, can be a cause of degenerative disorders. Since FADD/MORT1 is essential for apoptosis signalling from CD95 and some of its

Acknowledgements

Work in our laboratory is supported by fellowships from the Leukemia Society of America and Melbourne University and grants from the NHMRC (Canberra), the Dr. Josef Steiner Cancer Research Foundation (Bern), the Cancer Research Institute (New York) and the Anti-Cancer Council of Victoria (Melbourne).

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