Biology Reference
In-Depth Information
they respond with local activation and amplification of signals at the site
facing the gradient (cell polarity formation). These signals cause localized
polymerization of actin and formation of membrane protrusions such as
filopodia and lamellipodia (leading edge formation). These structures are
thought to generate the force for movement toward the gradient. Thus, it has
been of interest to understand how these structures are formed in response to
extracellular chemoattractants. Recent studies clarified the signalling path-
ways that link extracellular stimuli to actin polymerization at the leading edge.
One signalling cascade is governed by the small GTPases of the Rho family.
Among them, RhoA, Rac and Cdc42 play a critical role in the formation and
organization of cortical actin networks (Bishop and Hall, 2000; Hall, 1998).
RhoA controls assembly of stress fibres and focal adhesions. Rac regulates
formation of lamellipodia, and Cdc42 controls extension of filopodia and
microspikes. During cell movement, Rac and Cdc42 stimulate formation of
protrusions at the leading edges of cells, and RhoA induces retraction of the
tail ends of cells. This coordinated reorganization of actin filaments permits
cells to move toward a target. Though Rac and Cdc42 are essential for cell
movement, the downstream molecules involved directly in actin filament
reorganization were unknown until the WASp (Wiskott-Aldrich Syndrome
protein) family proteins were identified. These proteins have garnered a great
deal of attention as the links between the small GTPases and the actin
cytoskeleton. The WASp family proteins are classified into two structural
groups (Figure 9.1): WASps, which comprise WASp and N-WASp (Derry et
al., 1994; Miki et al., 1996; Fukuoka et al., 1997), and WAVEs (also called
Scar), which comprise WAVE1, 2 and 3 (Miki et al., 1998; Suetsugu et al.,
WASp and WAVE family proteins
WASp was first identified as the cause of Wiskott-Aldrich Syndrome (WAS),
which is characterized by eczema, bleeding and recurrent infections (Derry
et al., 1994). This protein is expressed exclusively in hematopoietic cells.
Lymphocytes from WAS patients show cytoskeletal abnormalities with a
reduction in the number of cell surface microvilli (Kenney et al., 1986; Molina
et al., 1992). WASp binds Cdc42 through its GBD/CRIB ( GT Pase- b inding
d omain/ C dc42 and R ac i nteractive b inding) motif, and overexpression of
WASp induces formation of actin clusters, suggesting a role in actin
polymerization (Symons et al., 1996). N-WASp was isolated as an Ash/
Grb2 SH3 domain-binding protein. This protein, in contrast to WASp, is
ubiquitously expressed in a variety of tissues, though it was named neural (N)-
WASp because of its high expression in neural tissues. N-WASp shows
approximately 50% amino-acid homology with WASp, and it contains several
Search WWH ::

Custom Search