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Gene Review

WASL  -  Wiskott-Aldrich syndrome-like

Homo sapiens

Synonyms: N-WASP, NWASP, Neural Wiskott-Aldrich syndrome protein
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Disease relevance of WASL


High impact information on WASL

  • Following the identification of WASP, the gene mutated in patients with this syndrome, and the more generally expressed WASP homologue N-WASP, studies have demonstrated that WASP-family molecules associate with numerous signaling molecules known to alter the actin cytoskeleton [5].
  • Microorganisms either activate Arp2/3 complex directly or usurp N-WASP to initiate actin polymerization [6].
  • Toca-1 binds both N-WASP and Cdc42 and is a member of the evolutionarily conserved PCH protein family [7].
  • Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich Syndrome [8].
  • Neural Wiskott-Aldrich syndrome protein (N-WASP) functions in several intracellular events including filopodium formation, vesicle transport and movement of Shigella frexneri and vaccinia virus, by stimulating rapid actin polymerization through the Arp2/3 complex [9].

Chemical compound and disease context of WASL


Biological context of WASL

  • Here, we show that heat shock protein 90 (HSP90) regulates N-WASP-induced actin polymerization in cooperation with phosphorylation of N-WASP [13].
  • Our data reveal a distinct cellular phenotype for N-WASP loss of function, which adds to accumulating evidence that the proposed link between actin and membrane dynamics may, at least partially, be reflected by the actin-based movement of vesicles through the cytoplasm [14].
  • Molecular genetic approaches demonstrate that Abi1 and WAVE, but not N-WASP, are essential for Rac-dependent membrane protrusion and macropinocytosis [15].
  • Neural Wiskott-Aldrich syndrome protein (N-WASP) has been implicated in endocytosis; however, little is known about how it interacts functionally with the endocytic machinery [16].
  • Although the WASP homology 1 (WH1) domain of N-WASP interacts directly with WIP, we still lack the exact nature of its binding site [17].

Anatomical context of WASL

  • WASP and its relative NWASP might play an important role in regulating the actin cytoskeleton [18].
  • These findings suggest that HSP90 induces efficient activation of N-WASP downstream of phosphorylation signal by Src family kinases and is critical for N-WASP-dependent podosome formation and neurite extension [13].
  • In a cell-free system, addition of active Cdc42 significantly stimulates the actin-depolymerizing activity of N-WASP, creating free barbed ends from which actin polymerization can then take place [19].
  • The presence of approximately 160 nmol/L rapidly acting N-WASP molecules may explain the normal capacity of WASP-negative patient platelets for early agonist-induced aggregation and filopodia formation [20].
  • WASP, a specific blood cell protein, and its close homologue, the broadly distributed N-WASP, function in dynamic actin polymerization processes [20].

Associations of WASL with chemical compounds

  • N-WASP is tightly regulated by multiple signals: Only costimulation by Cdc42 and phosphatidylinositol (4,5)-bisphosphate (PIP2) yields potent polymerization [21].
  • An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP [13].
  • Use of peptide inhibitors, mutated Grb2, and isolated SH3 domains demonstrate that the effect of Grb2 is mediated by the interaction of its C-terminal SH3 domain with the proline-rich region of N-WASp [22].
  • We report here that merlin and the ERMs can interact with and regulate N-WASP, a critical regulator of actin dynamics [23].
  • Reconstitution of vesicle movement in N-WASP-defective cells by expression of various N-WASP mutant proteins revealed three independent domains capable of interaction with the vesicle surface, of which both the WH1 and the polyproline domains contributed significantly to N-WASP recruitment and/or activation [14].

Physical interactions of WASL

  • TC10 exhibits sequence similarity to Cdc42 and has been reported to bind N-WASP [24].
  • Cdc42 and Grb2 bind simultaneously to N-WASp and enhance actin polymerization synergistically [22].
  • The verprolin-homology region in N-WASP was required for binding to the glycine-rich repeats domain of VirG, an essential domain for recruitment of F-actin on intracellular S.flexneri [1].
  • With respect to actin polymerization, our results indicate that the actin nucleation promoting factors (NPF) neural Wiskott-Aldrich syndrome protein (N-WASP) binds the SH2- plus SH3-domain containing adaptor protein Nck in both control and VEGF-treated cells [25].

Enzymatic interactions of WASL

  • In addition, HSP90 protects phosphorylated and activated N-WASP from proteasome-dependent degradation, resulting in amplification of N-WASP-dependent actin polymerization [13].

Regulatory relationships of WASL


Other interactions of WASL

  • Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex [21].
  • The ubiquitous homolog of WASp, N-WASp, is a multidomain protein that interacts with the Arp2/3 complex and G-actin via its C-terminal WA domain to stimulate actin polymerization [22].
  • Cdc42 and the actin-related protein/neural Wiskott-Aldrich syndrome protein network mediate cellular invasion by Cryptosporidium parvum [29].
  • In this review, the authors discuss the possible role of WASP/NWASP and of the newly described protein WIP, which interacts with WASP and NWASP, in coupling signals from the T-cell receptor to the actin-based cytoskeleton [18].
  • Interaction of HSP90 to N-WASP leads to activation and protection from proteasome-dependent degradation [13].

Analytical, diagnostic and therapeutic context of WASL

  • Immunofluorescence studies revealed that actin accumulates at sites where N-WASP and EA are co-localized after EGF stimulation [16].
  • Co-immunoprecipitation assays with anti-N-WASP antibody revealed that EGF induces association of N-WASP with EA [16].
  • Polystyrene microspheres, functionalized in a controlled fashion by the N-WASP protein, the ubiquitous activator of Arp2/3 complex, undergo actin-based propulsion in a medium that consists of five pure proteins [30].
  • Recent fluorescence resonance energy transfer (FRET) imaging experiments using activity biosensors show inconsistencies between the site of local activity of PAK1 or N-WASP and the formation of specific membrane protrusion structures in the cell periphery [31].
  • Consistent with a role of syndapins in linking actin polymerization bursts with endocytic vesicle formation, syndapin-containing complexes had a size of 300-500 kDa in gel filtration analysis and contained both dynamin and N-WASP [32].


  1. Neural Wiskott-Aldrich syndrome protein is implicated in the actin-based motility of Shigella flexneri. Suzuki, T., Miki, H., Takenawa, T., Sasakawa, C. EMBO J. (1998) [Pubmed]
  2. A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization. Moreau, V., Frischknecht, F., Reckmann, I., Vincentelli, R., Rabut, G., Stewart, D., Way, M. Nat. Cell Biol. (2000) [Pubmed]
  3. Actin-based motility of Burkholderia pseudomallei involves the Arp 2/3 complex, but not N-WASP and Ena/VASP proteins. Breitbach, K., Rottner, K., Klocke, S., Rohde, M., Jenzora, A., Wehland, J., Steinmetz, I. Cell. Microbiol. (2003) [Pubmed]
  4. Visualization of spatially and temporally regulated N-WASP activity during cytoskeletal reorganization in living cells. Ward, M.E., Wu, J.Y., Rao, Y. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Snapper, S.B., Rosen, F.S. Annu. Rev. Immunol. (1999) [Pubmed]
  6. Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins. Higgs, H.N., Pollard, T.D. Annu. Rev. Biochem. (2001) [Pubmed]
  7. Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex. Ho, H.Y., Rohatgi, R., Lebensohn, A.M., Le Ma, n.u.l.l., Li, J., Gygi, S.P., Kirschner, M.W. Cell (2004) [Pubmed]
  8. Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich Syndrome. Volkman, B.F., Prehoda, K.E., Scott, J.A., Peterson, F.C., Lim, W.A. Cell (2002) [Pubmed]
  9. IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Miki, H., Yamaguchi, H., Suetsugu, S., Takenawa, T. Nature (2000) [Pubmed]
  10. Profilin is required for sustaining efficient intra- and intercellular spreading of Shigella flexneri. Mimuro, H., Suzuki, T., Suetsugu, S., Miki, H., Takenawa, T., Sasakawa, C. J. Biol. Chem. (2000) [Pubmed]
  11. Differential roles for actin polymerization and a myosin II motor in assembly of the epithelial apical junctional complex. Ivanov, A.I., Hunt, D., Utech, M., Nusrat, A., Parkos, C.A. Mol. Biol. Cell (2005) [Pubmed]
  12. EspFU is a translocated EHEC effector that interacts with Tir and N-WASP and promotes Nck-independent actin assembly. Campellone, K.G., Robbins, D., Leong, J.M. Dev. Cell (2004) [Pubmed]
  13. Interaction of HSP90 to N-WASP leads to activation and protection from proteasome-dependent degradation. Park, S.J., Suetsugu, S., Takenawa, T. EMBO J. (2005) [Pubmed]
  14. Phosphatidylinositol 4,5-biphosphate (PIP2)-induced vesicle movement depends on N-WASP and involves Nck, WIP, and Grb2. Benesch, S., Lommel, S., Steffen, A., Stradal, T.E., Scaplehorn, N., Way, M., Wehland, J., Rottner, K. J. Biol. Chem. (2002) [Pubmed]
  15. Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes. Innocenti, M., Gerboth, S., Rottner, K., Lai, F.P., Hertzog, M., Stradal, T.E., Frittoli, E., Didry, D., Polo, S., Disanza, A., Benesch, S., Di Fiore, P.P., Carlier, M.F., Scita, G. Nat. Cell Biol. (2005) [Pubmed]
  16. Neural Wiskott-Aldrich syndrome protein is recruited to rafts and associates with endophilin A in response to epidermal growth factor. Otsuki, M., Itoh, T., Takenawa, T. J. Biol. Chem. (2003) [Pubmed]
  17. The WH1 and EVH1 domains of WASP and Ena/VASP family members bind distinct sequence motifs. Zettl, M., Way, M. Curr. Biol. (2002) [Pubmed]
  18. Waltzing with WASP. Ramesh, N., Antón, I.M., Martínez-Quiles, N., Geha, R.S. Trends Cell Biol. (1999) [Pubmed]
  19. Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP. Miki, H., Sasaki, T., Takai, Y., Takenawa, T. Nature (1998) [Pubmed]
  20. WASP and N-WASP in human platelets differ in sensitivity to protease calpain. Shcherbina, A., Miki, H., Kenney, D.M., Rosen, F.S., Takenawa, T., Remold-O'Donnell, E. Blood (2001) [Pubmed]
  21. Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex. Prehoda, K.E., Scott, J.A., Mullins, R.D., Lim, W.A. Science (2000) [Pubmed]
  22. GRB2 links signaling to actin assembly by enhancing interaction of neural Wiskott-Aldrich syndrome protein (N-WASp) with actin-related protein (ARP2/3) complex. Carlier, M.F., Nioche, P., Broutin-L'Hermite, I., Boujemaa, R., Le Clainche, C., Egile, C., Garbay, C., Ducruix, A., Sansonetti, P., Pantaloni, D. J. Biol. Chem. (2000) [Pubmed]
  23. The NF2 tumor suppressor Merlin and the ERM proteins interact with N-WASP and regulate its actin polymerization function. Manchanda, N., Lyubimova, A., Ho, H.Y., James, M.F., Gusella, J.F., Ramesh, N., Snapper, S.B., Ramesh, V. J. Biol. Chem. (2005) [Pubmed]
  24. A phosphatidylinositol 3-kinase-independent insulin signaling pathway to N-WASP/Arp2/3/F-actin required for GLUT4 glucose transporter recycling. Jiang, Z.Y., Chawla, A., Bose, A., Way, M., Czech, M.P. J. Biol. Chem. (2002) [Pubmed]
  25. VEGF treatment induces signaling pathways that regulate both actin polymerization and depolymerization. Gong, C., Stoletov, K.V., Terman, B.I. Angiogenesis (2004) [Pubmed]
  26. A neural Wiskott-Aldrich Syndrome protein-mediated pathway for localized activation of actin polymerization that is regulated by cortactin. Kempiak, S.J., Yamaguchi, H., Sarmiento, C., Sidani, M., Ghosh, M., Eddy, R.J., Desmarais, V., Way, M., Condeelis, J., Segall, J.E. J. Biol. Chem. (2005) [Pubmed]
  27. Activation of the CDC42 effector N-WASP by the Shigella flexneri IcsA protein promotes actin nucleation by Arp2/3 complex and bacterial actin-based motility. Egile, C., Loisel, T.P., Laurent, V., Li, R., Pantaloni, D., Sansonetti, P.J., Carlier, M.F. J. Cell Biol. (1999) [Pubmed]
  28. IQGAP1 Stimulates Actin Assembly through the N-Wasp-Arp2/3 Pathway. Le Clainche, C., Schlaepfer, D., Ferrari, A., Klingauf, M., Grohmanova, K., Veligodskiy, A., Didry, D., Le, D., Egile, C., Carlier, M.F., Kroschewski, R. J. Biol. Chem. (2007) [Pubmed]
  29. Cdc42 and the actin-related protein/neural Wiskott-Aldrich syndrome protein network mediate cellular invasion by Cryptosporidium parvum. Chen, X.M., Huang, B.Q., Splinter, P.L., Orth, J.D., Billadeau, D.D., McNiven, M.A., LaRusso, N.F. Infect. Immun. (2004) [Pubmed]
  30. A biomimetic motility assay provides insight into the mechanism of actin-based motility. Wiesner, S., Helfer, E., Didry, D., Ducouret, G., Lafuma, F., Carlier, M.F., Pantaloni, D. J. Cell Biol. (2003) [Pubmed]
  31. Spatially distinct binding of Cdc42 to PAK1 and N-WASP in breast carcinoma cells. Parsons, M., Monypenny, J., Ameer-Beg, S.M., Millard, T.H., Machesky, L.M., Peter, M., Keppler, M.D., Schiavo, G., Watson, R., Chernoff, J., Zicha, D., Vojnovic, B., Ng, T. Mol. Cell. Biol. (2005) [Pubmed]
  32. Syndapin oligomers interconnect the machineries for endocytic vesicle formation and actin polymerization. Kessels, M.M., Qualmann, B. J. Biol. Chem. (2006) [Pubmed]
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