title: Phosphorylation of WASp is a key regulator of activity and stability in vivo.
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.
authors.affiliation: Molecular Immunology Unit, Wolfson Centre for Gene Therapy of Childhood Disease and Centre for Immunodeficiency, UCL Institute of Child Health, London, WC1N 1EH, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Blundell
authors.forename: Gerben
authors.initials: G
authors.lastname: Bouma
authors.forename: Joao
authors.initials: J
authors.lastname: Metelo
authors.forename: Austen
authors.initials: A
authors.lastname: Worth
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Calle
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Cowell
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
authors.forename: Dale A
authors.initials: DA
authors.lastname: Moulding
authors.forename: Samuel
authors.initials: S
authors.lastname: Mirando
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Giles O
authors.initials: GO
authors.lastname: Cory
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.forename: Siobhan O
authors.initials: SO
authors.lastname: Burns
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000199:Actins / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002460:Cell Line; D002465:Cell Movement; D002522:Chlorocebus aethiops; D006410:Hematopoiesis; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D010587:Phagocytosis; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D011994:Recombinant Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D014443:Tyrosine