Biology Reference
In-Depth Information
Table 14.1 Putative focal adhesion and signalling
calpain substrates (reviewed in Glading et al., 2002
and Sato et al., 2001)
Adhesion complex
Signalling proteins
Talin
PKC
Filamin
RhoA
Paxillin
pp60Src
a-actinin
ZAP 70
b1 integrin
PTP1-B
b3 integrin
EGFR
b4 integrin
PLC-b
Vinculin
Ezrin
Spectrin
FAK
unlike other mechanisms in signal transduction such as phosphorylation
events, proteolysis involves an irreversible change to its substrate, a change
that to be effective during migration would have to be tightly regulated and
limited in its scope.
Many external factors can regulate calpain activity. There is evidence that
integrin ligation and signalling through the epidermal growth factor (EGF)
receptor can activate calpain activity in certain cell types (Glading et al.,
2001), while signalling through G-protein coupled receptors (GPCR) can
inhibit its activity (Shiraha et al., 1999). Calpain activity is regulated by
calpastatin, an endogenous calpain inhibitor. Calpastatin is highly specific for
m- and m-calpain and is ubiquitously expressed in cells. Calpain activity may
also be regulated by membrane phospholipids, with earlier studies indicating
that PIP
2
activates calpain activity (Arthur and Crawford, 1996; Saido et al.,
1992). There is some evidence that the ubiquitous calpain isoforms m- and
m-calpain may have distinct intracellular distributions. For instance, while
m-calpain has been found to localize to focal adhesions in some cell types
(Beckerle et al., 1987), m-calpain distribution tends to be diffuse throughout
the cytoplasm, although some studies have demonstrated localization to the
cell periphery in integrin-containing complexes (Bialkowska et al., 2000).
Recent studies have demonstrated that m-calpain, but not m-calpain, may be
segregated into lipid rafts, providing an additional mechanism to localize
calpain activity. A further mechanism that regulates calpain activity is
phosphorylation. For example, phosphorylation by protein kinase A (PKA)
can inhibit calpain activity, while recent evidence suggests that ERK-mediated
phosphorylation can activate calpain (Glading et al., 2002; Shiraha et al.,
2002).
