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Cross-talk between non receptor tyrosine kinases and caspases in cancer and in apoptosis
cleaved by caspases in this apoptotic response and how this event contributes
to the execution of the program. Our experiments may lead to the identification
of Arg as a new player of the apoptotic response and will help to understand
the mechanism that control anoikis.
PROPOSAL RELEVANCE
Our proposal is focused on the study of the molecular mechanisms that
allow the cross-regulation of two large families of proteins, the non receptor
tyrosine kinases and the caspases, that play a crucial role in the cellsurvival/cell-death
balance. The lack of this equilibrium is associated to severe
pathologies in humans. In particular, it has been well established that tumors
arise from the development of genetic modifications that affect genes implicated
in cell proliferation as well as in apoptosis control. Therefore the investigation
of the cross-talk of non receptor tyrosine kinases and caspases should
definitely have a primary relevance for cancer research.
The first part of the project is centred on the role of tyrosine kinases in the
control of caspases activity. Despite the absolute requirement for caspases
activity regulation in order to prevent undesired cell death, very little is known
about the molecular mechanisms that control and ensure this regulation. Tyrosine
phosphorylation has been shown to modulate the activity and the proteinprotein
interactions of several molecules and therefore to play a crucial role in
signal transduction in general. Some evidence suggests a role of tyrosine phosphorylation
in the apoptotic signal; one intriguing possibility is that tyrosine
kinases might directly phosphorylate and regulate the activity and the function
of caspases. We have recently identified the upstream activator Caspase-8 as a
new substrate of the proto-oncogene c-Src. Caspase-8 tyrosine phosphorylation
may severely affect Caspase-8 activity and function resulting in resistance
to death receptors-induced apoptosis. It is significant that Src kinase is often
up-regulated in tumors, especially in colon and breast cancers (14) . We identified
the presence of tyrosine phosphorylated Caspase-8 in human colon cancer.
The possibility that this event contributes to tumor progression and to tumor
resistance to chemotherapy and irradiation induced apoptosis is intriguing.
Support for this project might lead to the identification of a completely new
mechanism that allows Src kinase to contribute to tumor progression and to
the comprehension of a new mechanism that controls caspases activity and
function. Moreover, Caspase-8 Tyr380 phosphorylation may be clearly linked
with cancer and could be considered as a novel tumor marker.
The second part of the project is focused on the cross-talk of non receptor
tyrosine kinases and caspases in the control and execution of anoikis. Anoikis
is a programmed cell death caused by the loss of interactions of epithelial cells,
where caspases activation has been described. This mechanism ensures that
epithelial cells that have lost interaction with their extracellular matrix,
undergo cell death and prevents their migration. The comprehension of the
molecular mechanisms of anoikis is of particular importance for cancer
research, because anoikis resistance acquired by cancer cells, allows the formation
of metastasis.
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