Phosphorylation of WASp is a key regulator of activity and stability in vivo.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Wiskott-Aldrich Syndrome Protein/*metabolism; Actins/metabolism ; Amino Acid Substitution ; Animals ; Binding Sites/genetics ; COS Cells ; Cell Line ; Cell Movement ; Chlorocebus aethiops ; Hematopoiesis ; Humans ; In Vitro Techniques ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Mutagenesis, Site-Directed ; Phagocytosis ; Phosphorylation ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Tyrosine/chemistry ; Wiskott-Aldrich Syndrome/genetics ; Wiskott-Aldrich Syndrome/metabolism ; Wiskott-Aldrich Syndrome/pathology ; Wiskott-Aldrich Syndrome Protein/chemistry ; Wiskott-Aldrich Syndrome Protein/genetics
    • Abstract:
      The Wiskott-Aldrich syndrome protein (WASp) is a key cytoskeletal regulator in hematopoietic cells. Covalent modification of a conserved tyrosine by phosphorylation has emerged as an important potential determinant of activity, although the physiological significance remains uncertain. In a murine knockin model, mutation resulting in inability to phosphorylate Y293 (Y293F) mimicked many features of complete WASp-deficiency. Although a phosphomimicking mutant Y293E conferred enhanced actin-polymerization, the cellular phenotype was similar due to functional dysregulation. Furthermore, steady-state levels of Y293E-WASp were markedly reduced compared to wild-type WASp and Y293F-WASp, although partially recoverable by treatment of cells with proteasome inhibitors. Consequently, tyrosine phosphorylation plays a critical role in normal activation of WASp in vivo, and is indispensible for multiple tasks including proliferation, phagocytosis, chemotaxis, and assembly of adhesion structures. Furthermore, it may target WASp for proteasome-mediated degradation, thereby providing a default mechanism for self-limiting stimulation of the Arp2/3 complex.
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    • Grant Information:
      United Kingdom WT_ Wellcome Trust; 080373 United Kingdom WT_ Wellcome Trust; G0401026 United Kingdom MRC_ Medical Research Council
    • Accession Number:
      0 (Actins)
      0 (Recombinant Proteins)
      0 (Was protein, mouse)
      0 (Wiskott-Aldrich Syndrome Protein)
      42HK56048U (Tyrosine)
    • Publication Date:
      Date Created: 20091007 Date Completed: 20091113 Latest Revision: 20220129
    • Publication Date:
      20221213
    • Accession Number:
      PMC2736139
    • Accession Number:
      10.1073/pnas.0904346106
    • Accession Number:
      19805221