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the headpiece (Kd ΒΌ 7.410 6 M). A third, non-exchangeable high a nity
site, is located in the core domain. Binding of Ca 2+ to that located in the
headpiece induces a conformational change of the core part of the molecule
and thereby may induce a change in the molecule's biochemical behaviour.
Binding of PIP 2 to this sequence inhibits its interaction with actin. The
actin-binding site of the headpiece domain comprises a charged motif of
amino acids, KKEK (amino acids 820-823), which is conserved throughout
species (Friederich et al., 1992, 1999) and essential for its biological activities.
More recently, proteins containing a domain with similarities with the head
piece and which is likely to provide actin-binding activity, have been
identified. This includes the two subunits of dematin (Rana et al., 1993),
abLIM (Roof et al., 1997), supervillin (p205) (Pestonjamasp et al., 1997).
Moreover, among the gelsolin/villin family members, advillin (p92) is the only
one presenting a KKEK motif (Marks et al., 1998) and a conserved lysine at
position 815 in the headpiece domain. These sites have been shown to be
critical for actin binding (Doering and Matsudaira, 1996). The presence of
advillin in intestinal brush border could explain the absence of phenotype in
villin KO mice, compensating for villin actin bundling property.
Villin expression and brush border morphogenesis
Villin is a marker for a few cell types in adults and in embryos, and a
differentiation marker for epithelial cells displaying a brush border (for
reviews see Louvard, 1989; Heintzelman and Mooseker, 1992). During early
embryonic development in chicken and mouse, villin is detectable in cells of
the primitive gut which are precursors of the adult intestine. In adults, villin
synthesis increases during the differentiation process of the enterocyte, which
takes place when the enterocytes migrate along from crypt to the tip of the
intestinal villus. Moreover, villin expression is maintained in primary tumours
or metastases deriving from tissues which normally express villin. To
recapitulate the tissue-specific expression pattern of the endogenous villin
gene, we have shown that a 9 kb regulatory region of the mouse villin gene
contains the necessary cis-acting elements and can be used to drive the
expression of heterologous genes in immature and differentiated epithelial
cells of the small and/or large intestinal mucosa. C-met was reported directly
to interact with signalling proteins PLCg (Ponzetto et al., 1994). Furthermore,
it has been reported that villin interacts with several signalling molecules
including PLCg (Panebra et al., 2001), phosphatidylinositol 4,5-biphosphate
(PIP 2 ) (Janmey et al., 1987) and calcium (Janmey and Matsudaira, 1988).
In vitro, villin tyrosine phosphorylation has been shown to enhance actin
severing and to inhibit villin actin bundling property (Zhai et al., 2001). These
findings suggest that villin could play an essential role in the actin cytoskeleton
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