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Sezione III: Attività per progetti
We have recently identified c-Abl as a novel caspase substrate in apoptosis
upon death receptor stimulation. Caspases cleave c-Abl in the cytoplasmatic
compartment, generating a truncated Abl protein that lacks the
nuclear export signal and therefore accumulates in the nuclear compartment,
where Abl activity has a pro-apototic function. Abl caspase cleavage
causes the loss of a C-terminal region of the protein where a nuclear export
signal and an actin binding domain have been mapped (8-9) . These sequences
are also present in C-terminal portion of Arg, the Abl Related Gene product.
Abl and Arg constitute the Abl family of non receptor tyrosine kinases, characterized
by binding to F-actin. Indeed these proteins have a crucial function
in the regulation of many F-actin-dependent processes, such as cell death,
cell adhesion, cell migration and neurite extension. Since anoikis is induced
by a loss of cell adhesion activation of we will test the possibility that caspase
cleavage recruits the Abl family proteins to this apoptotic response. Support
for this project is essential to allow studies on molecular mechanisms of
anoikis and will help to clarify Arg’s putative role in the apoptotic signal
transduction.
BACKGROUND AND RATIONALE
Non receptor tyrosine kinases and caspases are two large families of proteins
that play a central role in the regulation of cell survival and cell death.
Some evidence supports the idea of a cross-talk between these molecules. Caspase
cleavage can induce the activity of many non receptor tyrosine kinases
during apoptosis (6-7) and, tyrosine phosphorylation can modulate the apoptotic
signal (15-18) . Caspases might be phosphorylated on serine and threonine,
and phosphorylation affects their activity (2,19) .
Caspases – Caspases are a family of cystein-proteases highly conserved
through evolution. All known caspases cleave substrates after an aspartic acid
residue. These enzymes are activated by several stimuli and trigger all the morphological
and biochemical changes resulting in the systematic and orderly
disassembly of the dying cell into apoptotic bodies (20) . Caspases are synthesized
as enzymatically inactive proenzymes composed of three domains: an
N-terminal prodomain, a large subunit and a small subunit. Their activation
occurs through a series of proteolytic cleavages always mediated by caspases
that result in the release of the prodomain and assembly of an active tetramer
composed of two large and two small subunits (21-22) .
Fas (CD95) death receptor – The transmembrane Fas receptor belongs to
the death receptor family. These molecules are activated upon specific ligand
binding (23) , which triggers the assembly of a complex of adaptor proteins that
induce oligomerization of the upstream activator Caspase-8 and caspase-10 (24) .
This complex is named Death-Inducing Signaling Complex (DISC). According
to this model, caspases’ recruitment to the DISC results in their self-cleavage
and self-activation that then triggers the cleavage and activation of more downstream
executor caspases. These finally cleave several cellular substrates leading
to the execution of the apoptotic program.
624 2006