| Literature References | 1. GOLDSBY, R.A., KINDT, T.J. AND OSBORNE, B.A.
Kuby immunology.
W.H.FREEMAN AND COMPANY, 2000, pp.260-261, 503-504.
2. WENZEL, J., SANZENBACHER, R., GHADIMI, M., ZHOU, Q., KAPLAN, D.R.,
KABELITZ, D., FELLER, S.M. AND JANSSEN, O.
Multiple interactions of the cytosolic polyproline region of the CD95 ligand:
hints for the reverse signal tranduction capacity of a death factor.
FEBS LETT. 509 255-262 (2001).
3. YANKEE, T.M., DRAVES, K.E., EWINGS, M.K., CLARK, E.A. AND GRAVES, J.D.
CD95/Fas induces cleavage of the GrpL/Gads adaptor and desensitization of
antigen receptor signaling.
PROC.NATL.ACAD.SCI.U.S.A. 98 6789-6793 (2001).
4. TAKAHASHI, T., TANAKA, M., INAZAWA, J., ABE, T., SUDA, T. AND NAGATA, S.
Human Fas ligand: gene strucure, chromosomal location and species specificity.
INT.IMMUNOL. 6 1567-1574 (1994).
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| Documentation | Like all apoptotic cell death, T cell receptor (TCR)-mediated death can be
divided into two phases: an inductive phase and an effector phase. The
effector phase includes a sequence of steps that are common to apoptosis in
many cell types, which, if not interrupted, will lead to cell death. The
induction phase, which often requires the expression of new genes, consists
of a set of signals that activate the effector phase. Outside the thymus,
most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimes
referred to as activation-induced cell death (AICD)) is induced through the
surface antigen Fas pathway: activation through the TCR induces expression
of the Fas (CD95) ligand (FasL); the expression of FasL on either a
neighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas,
which then initiates a signal-transduction cascade, leading to apoptosis of
the Fas-bearing cell. This commitment stage requires the activation of key
death-inducing enzymes, termed caspases, which act by cleaving proteins that
are essential for cell survival and proliferation [1,2]. However what
happens to FasL itself remains unknown. It is possible that it is cleaved
from the effector cells and internalised into the target cells; it may be
downregulated in the effector cells; or it may be phagocytosed by the target
cells [1-4].
Fas is also known to be essential in the death of hyperactivated peripheral
CD4+ cells: in the absence of Fas, mature peripheral T cells do not die, but
the activated cells continue to proliferate, producing cytokines that lead
to grossly enlarged lymph nodes and spleen. Defects in the Fas-FasL system
are associated with various disease syndromes. Mice with non-functional Fas
or FasL display characteristics of lymphoproliferative disorder, such as
lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. These
mice also secrete anti-DNA autoantibodies and rheumatoid factor [3].
FasL is a 40kDa type II membrane protein belonging to the tumour necrosis
factor (TNF) family. It is expressed on activated lymphocytes, NK cells,
platelets, certain immune-privileged cells and some tumour cells [1,3].
Human and mouse FasL induce apoptosis in cells expressing either mouse or
human Fas with the same specificity. Although the amino acid sequence of
FasL is highly conserved between human and mouse, the similarity between
human and murine Fas is much less pronounced. Greater conservation of the
ligand than the receptor is also observed in other members of the TNF family.
By comparison with other TNF family members, FasL has a long N-terminal
intracellular region rich in proline residues, which is known to bind to
the SH3 domain. SH3 domains play important roles in mediating specific
protein-protein interactions, specifically in the cytoskeleton [1].
FASLIGAND is a 7-element fingerprint that provides a signature for the Fas
antigen ligand. The fingerprint was derived from an initial alignment of 5
sequences: the motifs were drawn from conserved sequences spanning virtually
the full alignment length - motif 1 lies in the N-terminal cytoplasmic
region; motif 2 includes the C-terminus of the type-II membrane protein
signal sequence; and motifs 3-7 span the extracellular domain. A single
iteration on SPTR39_17f was required to reach convergence, no further
sequences being identified beyond the starting set. Two partial matches
were found, Q9BZP9 and Q99PH8, truncated human and murine FasL isoforms
that lack the portion of sequence bearing the last 5 motifs.
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