Biology Reference
In-Depth Information
Several Rac1 GEFs contain pleckstrin homology motifs that bind PI
3-kinase targets and may serve to localize or activate GEFs at sites of PI
3-kinase activity. One example is Tiam1, a Rac1-specific GEF which localizes
to cell-cell junctions and is sensitive to PI 3-kinase inhibitors (Hordijk et al.,
1997; Sander et al., 1998). Another example is Vav, a GEF reported to activate
Rac1 downstream of PI 3-kinase (Gringhuis et al., 1998). The Vav2 isoform
binds p120 catenin, possibly localizing the GEF to cell-cell contacts through
the interaction of p120 with E-cadherin (Noren et al., 2000). IQGAP, a
putative binding partner of Rac1, also associates with developing cell-cell
adhesions (Nakagawa et al., 2001; Fukata et al., 1999; Kuroda et al., 1998,
1999). IQGAP is thought to bind b-catenin and block its interaction with a-
catenin, preventing linkage of E-cadherin to actin. Active Rac1 could compete
with b-catenin for IQGAP, releasing b-catenin to bind a-catenin and thus
linking cadherin to the cytoskeleton to form strong adhesions.
Another mechanism by which Rac1 and Cdc42 could affect cell-cell contacts
is by regulating actin structure and dynamics. Of particular interest is the
Cdc42-WASp-Arp2/3 pathway, which has been particularly well defined
(Higgs and Pollard, 2001; Prehoda et al., 2000; Rohatgi et al., 1999). Cdc42 and
PIP2 bind WASp coordinately, resulting in a conformational change in WASp
(Higgs and Pollard, 2001), and allowing WASp to bind the Arp2/3 complex via
its VCA domain (Hufner et al., 2001). Normally weak Arp2/3 activity in
initiating actin polymerization is dramatically increased by WASp binding
(Higgs and Pollard, 2001; Prehoda et al., 2000; Machesky and Insall, 1998).
Rac1-mediated activation of Arp2/3 in lamellipodia is thought to occur in a
similar mechanism involving WAVE/Scar proteins and IRSp53 (Miki et al.,
2000). Recently, Arp2/3 binding and regulation by Abp1 in response to Rac1
activity has been reported (Goode et al., 2001; Kessels et al., 2000). Thus,
structural diversity generated by Arp2/3 activation may arise by orchestrating
reactions between different binding proteins (Higgs and Pollard, 2001).
Acknowledgements
J.S.E. was supported by the Medical Scientist Training Program (grant
5T32GM07365 from the National Institute of General Medical Sciences),
M.D.H.H. was supported by the Smith Fellowship in the Stanford Graduate
Fellowship Program and the Cancer Biology Graduate Program, and work
was also supported by NIH grant GM35527 to W.J.N.
References
Abercrombie, M., Heaysman, J. E. and Pegrum, S. M., 1970a. The locomotion of
fibroblasts in culture. I. Movements of the leading edge. Exptl. Cell Res. 59: 393-398.
