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Cross-talk between non receptor tyrosine kinases and caspases in cancer and in apoptosis
Src family kinases and tumor progression – The Src family of non-receptor
protein tyrosine kinases plays critical role in a variety of cellular signal transduction
pathways, regulating such diverse processes as cell division, motility,
adhesion, angiogenesis, and survival. Constitutively activated Src variants,
induce malignant transformation of variety of cell types. Src family kinases,
are often aberrantly activated in a variety of epithelial and non-epithelial cancers,
such as, colorectal and breast cancers (5) . Further, the extent of increased
Src family activity often correlates with malignant potential and patient survival.
Exactly how Src family kinases contribute to individual tumors remains
to be defined completely. However, they appear to be important for multiple
aspects of tumor progression, including proliferation, disruption of cell/cell
contacts, migration, invasiveness, resistance to apoptosis, and angiogenesis (25) .
Role of protein phosphorylation in the control and execution of apoptosis –
The function of many components of the apoptotic machinery is modulated
through serine/threonine phosphorylation. Very little is known about caspases’
phosphorylation. It has been shown that Akt and MAPK can phosphorylate
and repress caspase-9 activity (2) , while p38 has been proposed to modulate caspase-3
and Caspase-8 activity (4) . Tyrosine kinases have been reported to modulate
Fas-induced apoptosis (15-16) . However, none of the caspases or of the Bcl2
family members have been yet identified as direct substrates of tyrosine
kinases.
Src family kinases trigger Caspase-8 tyrosine phosphorylation and modulate
its activity – We identified Caspase-8 as a new substrate for Src kinase. Phosphorylation
occurs on Tyr380, situated in the linker region between the large
and the small subunits of human Procaspase-8, and results in down-regulation
of Caspase-8 proapototic function. Src activation triggers Caspase-8 phosphorylation
on Tyr380 and impairs Fas-induced apoptosis. Accordingly, Src failed
to protect Caspase-8-defective human cells in which a Caspase-8-Y380F
mutant is expressed from Fas-induced cell death.
Remarkably, Src activation upon EGF-receptor stimulation, triggers
endogenous Caspase-8 phosphorylation and prevents Fas-induced apoptosis.
Tyr380 is phosphorylated also in human colon cancers where Src is aberrantly
activated. These data provide the first evidence for a direct role of tyrosine
phosphorylation in the control of caspases and reveal a new mechanism
through which tyrosine kinases inhibit apoptosis and participate in tumor progression.
These data suggest that Src kinases could modulate apoptosis
through direct phosphorylation of Caspase-8. This event might play a role in
tumorigenesis and might be targeted for the development of new therapeutic
approaches (14) .
Anoikis – The loss of cell anchorage to cell matrix of normally adherent
cells triggers a particular form of apoptosis, named anoikis. Understanding
anoikis is particularly relevant for cancer research since malignant cells, once
they begin to metastasize, have obviously acquired properties rendering them
resistant to loss of cell anchorage and anoikis, because they are able to detach
from the primary tumor without undergoing apoptosis. The molecular mechanisms
that regulate anoikis are still largely obscure. Evidences for a clear role
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