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Gene Review

WAS  -  Wiskott-Aldrich syndrome

Homo sapiens

Synonyms: IMD2, SCNX, THC, THC1, WASP, ...
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Disease relevance of WAS


Psychiatry related information on WAS


High impact information on WAS


Chemical compound and disease context of WAS


Biological context of WAS

  • Rac signalling to actin -- a pathway that is thought to be mediated by the protein Scar/WAVE (WASP (Wiskott-Aldrich syndrome protein)-family verprolin homologous protein -- has a principal role in cell motility [17].
  • By contrast, mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation [18].
  • The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis [19].
  • Here, however, we show that T cell development and T cell receptor (TCR)-induced proliferation and actin polymerization proceed normally in WASp-/- mice expressing a WASp transgene lacking the cdc42 binding domain [18].
  • In addition, we provide information on the molecular mechanisms that control WASp function, demonstrating that binding of NK cells to sensitive targets or triggering through CD16 by means of reverse antibody-dependent cellular cytotoxicity (ADCC) rapidly activates Cdc42 [20].

Anatomical context of WAS


Associations of WAS with chemical compounds


Physical interactions of WAS


Enzymatic interactions of WAS


Co-localisations of WAS

  • We found that WASp colocalizes with CDC42Hs and actin in the core of podosomes, a highly dynamic adhesion structure of human blood-derived macrophages [33].

Regulatory relationships of WAS


Other interactions of WAS

  • Here, we describe a mechanism that ensures rapid and selective long-range Cdc42-WASp recognition [36].
  • Wiskott-Aldrich-syndrome mutations in the WA domain that alter nucleation by the Arp2/3 complex over a tenfold range without affecting affinity for actin or the Arp2/3 complex indicate that there may be an activation step in the nucleation pathway [34].
  • We identified one of the major phosphoproteins associated with Btk in the preB cell line NALM6 as the Wiskott-Aldrich syndrome protein (WASP), the gene product responsible for Wiskott-Aldrich syndrome, which is another hereditary immunodeficiency with distinct abnormalities in hematopoietic cells [24].
  • 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 [37].
  • Consistently, macrophages microinjected with CIP4 constructs deficient in either the microtubule- or the WASp-binding domain also fail to reassemble podosomes [27].

Analytical, diagnostic and therapeutic context of WAS


  1. CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk. Oda, A., Ochs, H.D., Lasky, L.A., Spencer, S., Ozaki, K., Fujihara, M., Handa, M., Ikebuchi, K., Ikeda, H. Blood (2001) [Pubmed]
  2. Cdc42-interacting protein 4 mediates binding of the Wiskott-Aldrich syndrome protein to microtubules. Tian, L., Nelson, D.L., Stewart, D.M. J. Biol. Chem. (2000) [Pubmed]
  3. Regulation and function of WASp in platelets by the collagen receptor, glycoprotein VI. Gross, B.S., Wilde, J.I., Quek, L., Chapel, H., Nelson, D.L., Watson, S.P. Blood (1999) [Pubmed]
  4. Yersinia enterocolitica invasin triggers phagocytosis via beta1 integrins, CDC42Hs and WASp in macrophages. Wiedemann, A., Linder, S., Grassl, G., Albert, M., Autenrieth, I., Aepfelbacher, M. Cell. Microbiol. (2001) [Pubmed]
  5. T cell lines characterize events in the pathogenesis of the Wiskott-Aldrich syndrome. Molina, I.J., Kenney, D.M., Rosen, F.S., Remold-O'Donnell, E. J. Exp. Med. (1992) [Pubmed]
  6. Possible involvement of Wiskott-Aldrich syndrome protein family in aberrant neuronal sprouting in Alzheimer's disease. Kitamura, Y., Tsuchiya, D., Takata, K., Shibagaki, K., Taniguchi, T., Smith, M.A., Perry, G., Miki, H., Takenawa, T., Shimohama, S. Neurosci. Lett. (2003) [Pubmed]
  7. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Snapper, S.B., Rosen, F.S. Annu. Rev. Immunol. (1999) [Pubmed]
  8. 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]
  9. 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]
  10. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Devriendt, K., Kim, A.S., Mathijs, G., Frints, S.G., Schwartz, M., Van Den Oord, J.J., Verhoef, G.E., Boogaerts, M.A., Fryns, J.P., You, D., Rosen, M.K., Vandenberghe, P. Nat. Genet. (2001) [Pubmed]
  11. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Villa, A., Notarangelo, L., Macchi, P., Mantuano, E., Cavagni, G., Brugnoni, D., Strina, D., Patrosso, M.C., Ramenghi, U., Sacco, M.G. Nat. Genet. (1995) [Pubmed]
  12. Correlation between interleukin-1 production and engraftment of transplanted bone marrow stem cells in patients with lethal immunodeficiencies. Sahdev, I., O'Reilly, R., Hoffman, M.K. Blood (1989) [Pubmed]
  13. Treatment of acyclovir-resistant herpes simplex virus keratitis in a patient with Wiskott-Aldrich syndrome. Pratuangtham, S., Bornstein, S.M., Boyer, K.M., McAuley, J.B., Deutsch, T.A., Gotoff, S.P. Clin. Infect. Dis. (1997) [Pubmed]
  14. Positive gallium-67 citrate scintigraphy in Wiskott-Aldrich syndrome with malignant lymphoma. Sandrock, D., Lastoria, S., Merino, M.J., Neumann, R.D. European journal of nuclear medicine. (1991) [Pubmed]
  15. Progressive varicella in three patients with Wiskott-Aldrich syndrome: treatment with adenine arabinoside. Wade, N.A., Lepow, M.L., Veazey, J., Meuwissen, H.J. Pediatrics (1985) [Pubmed]
  16. Bacteremia due to beta-lactamase-producing Enterococcus faecalis with high-level resistance to gentamicin in a child with Wiskott-Aldrich syndrome. Mazzulli, T., King, S.M., Richardson, S.E. Clin. Infect. Dis. (1992) [Pubmed]
  17. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Eden, S., Rohatgi, R., Podtelejnikov, A.V., Mann, M., Kirschner, M.W. Nature (2002) [Pubmed]
  18. Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. Badour, K., Zhang, J., Shi, F., Leng, Y., Collins, M., Siminovitch, K.A. J. Exp. Med. (2004) [Pubmed]
  19. The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis. McGavin, M.K., Badour, K., Hardy, L.A., Kubiseski, T.J., Zhang, J., Siminovitch, K.A. J. Exp. Med. (2001) [Pubmed]
  20. Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect. Gismondi, A., Cifaldi, L., Mazza, C., Giliani, S., Parolini, S., Morrone, S., Jacobelli, J., Bandiera, E., Notarangelo, L., Santoni, A. Blood (2004) [Pubmed]
  21. The Wiskott-Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Badour, K., Zhang, J., Shi, F., McGavin, M.K., Rampersad, V., Hardy, L.A., Field, D., Siminovitch, K.A. Immunity (2003) [Pubmed]
  22. Activation by Cdc42 and PIP(2) of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex. Higgs, H.N., Pollard, T.D. J. Cell Biol. (2000) [Pubmed]
  23. A conserved amphipathic helix in WASP/Scar proteins is essential for activation of Arp2/3 complex. Panchal, S.C., Kaiser, D.A., Torres, E., Pollard, T.D., Rosen, M.K. Nat. Struct. Biol. (2003) [Pubmed]
  24. Involvement of wiskott-aldrich syndrome protein in B-cell cytoplasmic tyrosine kinase pathway. Baba, Y., Nonoyama, S., Matsushita, M., Yamadori, T., Hashimoto, S., Imai, K., Arai, S., Kunikata, T., Kurimoto, M., Kurosaki, T., Ochs, H.D., Yata, J., Kishimoto, T., Tsukada, S. Blood (1999) [Pubmed]
  25. Normal Arp2/3 complex activation in platelets lacking WASp. Falet, H., Hoffmeister, K.M., Neujahr, R., Hartwig, J.H. Blood (2002) [Pubmed]
  26. Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways. Cory, G.O., MacCarthy-Morrogh, L., Banin, S., Gout, I., Brickell, P.M., Levinsky, R.J., Kinnon, C., Lovering, R.C. J. Immunol. (1996) [Pubmed]
  27. Microtubule-dependent formation of podosomal adhesion structures in primary human macrophages. Linder, S., Hüfner, K., Wintergerst, U., Aepfelbacher, M. J. Cell. Sci. (2000) [Pubmed]
  28. Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases. Banin, S., Truong, O., Katz, D.R., Waterfield, M.D., Brickell, P.M., Gout, I. Curr. Biol. (1996) [Pubmed]
  29. Influence of the C terminus of Wiskott-Aldrich syndrome protein (WASp) and the Arp2/3 complex on actin polymerization. Higgs, H.N., Blanchoin, L., Pollard, T.D. Biochemistry (1999) [Pubmed]
  30. Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein. Abdul-Manan, N., Aghazadeh, B., Liu, G.A., Majumdar, A., Ouerfelli, O., Siminovitch, K.A., Rosen, M.K. Nature (1999) [Pubmed]
  31. A WASp-VASP complex regulates actin polymerization at the plasma membrane. Castellano, F., Le Clainche, C., Patin, D., Carlier, M.F., Chavrier, P. EMBO J. (2001) [Pubmed]
  32. Protein-tyrosine kinase and GTPase signals cooperate to phosphorylate and activate Wiskott-Aldrich syndrome protein (WASP)/neuronal WASP. Torres, E., Rosen, M.K. J. Biol. Chem. (2006) [Pubmed]
  33. Wiskott-Aldrich syndrome protein regulates podosomes in primary human macrophages. Linder, S., Nelson, D., Weiss, M., Aepfelbacher, M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  34. Interaction of WASP/Scar proteins with actin and vertebrate Arp2/3 complex. Marchand, J.B., Kaiser, D.A., Pollard, T.D., Higgs, H.N. Nat. Cell Biol. (2001) [Pubmed]
  35. The Wiskott-Aldrich syndrome protein regulates nuclear translocation of NFAT2 and NF-kappa B (RelA) independently of its role in filamentous actin polymerization and actin cytoskeletal rearrangement. Huang, W., Ochs, H.D., Dupont, B., Vyas, Y.M. J. Immunol. (2005) [Pubmed]
  36. An electrostatic steering mechanism of Cdc42 recognition by Wiskott-Aldrich syndrome proteins. Hemsath, L., Dvorsky, R., Fiegen, D., Carlier, M.F., Ahmadian, M.R. Mol. Cell (2005) [Pubmed]
  37. 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]
  38. Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. Wiskott-Aldrich Syndrome protein. Cory, G.O., Garg, R., Cramer, R., Ridley, A.J. J. Biol. Chem. (2002) [Pubmed]
  39. WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Imai, K., Nonoyama, S., Ochs, H.D. Current opinion in allergy and clinical immunology. (2003) [Pubmed]
  40. Visualizing Arp2/3 complex activation mediated by binding of ATP and WASp using structural mass spectrometry. Kiselar, J.G., Mahaffy, R., Pollard, T.D., Almo, S.C., Chance, M.R. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  41. Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains. Rivero-Lezcano, O.M., Marcilla, A., Sameshima, J.H., Robbins, K.C. Mol. Cell. Biol. (1995) [Pubmed]
  42. Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment. Sabri, S., Foudi, A., Boukour, S., Franc, B., Charrier, S., Jandrot-Perrus, M., Farndale, R.W., Jalil, A., Blundell, M.P., Cramer, E.M., Louache, F., Debili, N., Thrasher, A.J., Vainchenker, W. Blood (2006) [Pubmed]
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