Trends in Cell Biology
ReviewsWaltzing with WASP
Section snippets
WASP and NWASP
By using a positional-cloning strategy, the gene responsible for the Wiskott–Aldrich syndrome was identified5; the WAS gene encodes a 502-residue, proline-rich protein, WASP (see Fig. 1). WASP contains an N-terminal pleckstrin-homology (PH) domain, which partially overlaps with a WASP-homology (WH) domain, WH1, found in several proteins, including Ena, Mena, Evl and vasodilator-stimulated phosphoprotein (VASP), that are involved in the maintenance of cytoskeletal integrity6, 7. The WH1 domain
Molecular interactions of WASP/NWASP
The amino acid sequence of WASP contains several protein–protein interaction motifs that could mediate its interaction with other molecules. WASP binds via its GBD domain to Cdc42 and weakly to Rac but not to Rho6, 10, 11. Recent biochemical studies have shown that the GBD domain is necessary but not sufficient for high-affinity binding to Cdc42, indicating that other regions of WASP also contribute to this interaction12. Overexpression of WASP induces the formation of actin-containing
WIP
Yeast two-hybrid screening using WASP as a bait led to the identification of the novel protein WIP (WASP-interacting protein)20. WIP is a proline-rich 503-residue protein with a calculated mass of 52 kDa. The N-terminal region contains two stretches, 28 residues (residues 32–59) and 17 residues (96–112) in length, that are highly homologous to residues 30–57 and 88–104, respectively, in the N-terminal region of the yeast protein verprolin20—verprolin-homology (VH) domains. Verprolin appears to
WIP interacts with WASP
WASP and WIP expressed as recombinant bacterial fusion proteins bind to each other, indicating that posttranslational modification of these proteins is not necessary for their interaction. WASP co-immunoprecipitates with WIP from cell lysates, further suggesting that WIP and WASP associate within cells. WIP binds to WASP at the N- terminal region, at a site distinct from the Cdc42-binding site. Curiously, the majority of point mutations in patients with WAS are located in the WH1 domain,
Small GTPases are essential for signal transduction to the actin-based cytoskeleton
Small GTPases of the Rho family are important regulators of the dynamics of the actin cytoskeleton27. The current paradigm, based on extensive experiments performed using Swiss 3T3 cells, shows that Cdc42 induces formation of filopodia, Rac causes formation of lamellipodia and Rho induces formation of stress fibres and is crucial for the assembly and maintenance of focal adhesion complexes. Rac and Cdc42 induce smaller focal complexes that are associated with lamellipodia and filopodia28. It is
The Rho family of small GTPases in lymphoid cells
There is extensive evidence for the role of Rho in stress fibre formation in adherent cells. By contrast, very little is known about the role of Rho in lymphocytes. The expression of Clostridium botulinum C3 toxin, which selectively ADP ribosylates Asp41 and inactivates Rho, as a transgene in the thymus, leads to a severe reduction in the number of thymocytes and circulating peripheral T cells31. There are fewer pro-T cells (CD44+/CD25+) and pre-T cells (CD44−/CD25+) cells32. Bcl-2 expression
How might WASP and WIP link TCR-originated signals to the actin cytoskeleton?
Lymphocyte activation through TCR–CD3 is defective in WAS patients. Ligation of TCR–CD3 results in an increase of the F-actin content of T cells; however, T cell lines from WAS patients do not show this increase38, indicating a link between WASP and the TCR. Furthermore, T cells from WAS patients show a paucity of surface structures, such as microvilli, as assessed by scanning electron microscopy1. Taken together, these observations suggest that WASP might serve as a focal point to collect
Concluding remarks
Information on the cellular function(s) of WASP/NWASP is beginning to emerge, but there are still many gaps in our understanding. It is not known whether the many molecules that bind to WASP/NWASP bind together, in groups or in a defined order. For example, the Cdc42-binding site and the WIP-binding sites on WASP/NWASP are different, but, as there is no evidence for a ternary complex of Cdc42–WIP–WASP, Cdc42 and WIP proteins could bind to WASP/NWASP in a discrete order—binding of one protein
Note added in proof:
Since writing this review, it has come to light that the Arp2/3 complex interacts with a conserved acidic motif C-terminal to the WH2 domain of WASP and a WASP-related protein named Scar158. The WASP-binding protein WIP also has a WH2 domain and sequences that could interact with the Arp2/3 complex. It will be interesting to test whether WIP could bind to the Arp2/3 complex and how WASP and WIP could participate in the regulation of actin dynamics through the Arp2/3 complex.
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2006, ImmunityCitation Excerpt :The requirement for T cell help may differ as high levels of IgE have been observed in unmanipulated athymic mice (Ito et al., 1979; Savelkoul et al., 1989) and strains deficient for αβ+ T cells (Wen et al., 1994) or the linker for activation of T cells (LAT) adaptor protein (Aguado et al., 2002). In man, T cell immunodeficiency can also be associated with high serum IgE, for example in Hyper-IgE syndrome (Buckley, 2001), Wiskott-Aldrich syndrome (WAS) (Ochs, 2001; Ramesh et al., 1999), DiGeorge anomaly (Buckley, 2002), and Ommen's syndrome (Villa et al., 1998), usually without a clear infective cause. We show here that natural IgE is spontaneously produced in the serum of wt germ-free animals and becomes elevated in T cell-deficient mouse strains.
The platelet cytoskeleton
2006, Platelets, Second Edition