Phosphorylation of WASp is a Key Regulator of Activity and Stability in Vivo

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Oct 7

PMID 19805221

Citations 35

Authors

Michael P Blundell

Gerben Bouma

Joao Metelo

Austen Worth

Yolanda Calle

Lucy A Cowell

Lisa S Westerberg

Dale A Moulding

Samuel Mirando

Christine Kinnon

Giles O Cory

Gareth E Jones

Scott B Snapper

Siobhan O Burns

Adrian J Thrasher

Affiliations

Soon will be listed here.

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.

Citing Articles

Glycogen synthase kinase 3 inhibition controls infection.

Pena-Diaz S, Chao J, Rens C, Haghdadi H, Zheng X, Flanagan K iScience. 2024; 27(8):110555.

PMID: 39175770 PMC: 11340618. DOI: 10.1016/j.isci.2024.110555.

CRISPR/Cas9-mediated deletion of the Wiskott-Aldrich syndrome locus causes actin cytoskeleton disorganization in murine erythroleukemia cells.

Fernandez-Calleja V, Fernandez-Nestosa M, Hernandez P, Schvartzman J, Krimer D PeerJ. 2019; 7:e6284.

PMID: 30671311 PMC: 6339507. DOI: 10.7717/peerj.6284.

Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive.

Keszei M, Record J, Kritikou J, Wurzer H, Geyer C, Thiemann M J Clin Invest. 2018; 128(9):4115-4131.

PMID: 30124469 PMC: 6118594. DOI: 10.1172/JCI64772.

Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity.

Rivers E, Thrasher A Eur J Immunol. 2017; 47(11):1857-1866.

PMID: 28805251 PMC: 7612068. DOI: 10.1002/eji.201646715.

Cytoskeletal control of B cell responses to antigens.

Tolar P Nat Rev Immunol. 2017; 17(10):621-634.

PMID: 28690317 DOI: 10.1038/nri.2017.67.

References

Park S, Suetsugu S, Takenawa T . Interaction of HSP90 to N-WASP leads to activation and protection from proteasome-dependent degradation. EMBO J. 2005; 24(8):1557-70. PMC: 1142563. DOI: 10.1038/sj.emboj.7600586. View

Lorenzi R, Brickell P, Katz D, Kinnon C, Thrasher A . Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis. Blood. 2000; 95(9):2943-6. View

Dunn G, Jones G . Cell motility under the microscope: Vorsprung durch Technik. Nat Rev Mol Cell Biol. 2004; 5(8):667-72. DOI: 10.1038/nrm1439. View

Kato M, Miki H, Imai K, Nonoyama S, Suzuki T, Sasakawa C . Wiskott-Aldrich syndrome protein induces actin clustering without direct binding to Cdc42. J Biol Chem. 1999; 274(38):27225-30. DOI: 10.1074/jbc.274.38.27225. View

Curtis A . THE MECHANISM OF ADHESION OF CELLS TO GLASS. A STUDY BY INTERFERENCE REFLECTION MICROSCOPY. J Cell Biol. 1964; 20:199-215. PMC: 2106393. DOI: 10.1083/jcb.20.2.199. View

Westerberg L, Wallin R, Greicius G, Ljunggren H, Severinson E . Efficient antigen presentation of soluble, but not particulate, antigen in the absence of Wiskott-Aldrich syndrome protein. Immunology. 2003; 109(3):384-91. PMC: 1782978. DOI: 10.1046/j.1365-2567.2003.01668.x. View

Suetsugu S, Hattori M, Miki H, Tezuka T, Yamamoto T, Mikoshiba K . Sustained activation of N-WASP through phosphorylation is essential for neurite extension. Dev Cell. 2002; 3(5):645-58. DOI: 10.1016/s1534-5807(02)00324-6. View

Badour K, Zhang J, Shi F, Leng Y, Collins M, Siminovitch K . 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. J Exp Med. 2004; 199(1):99-112. PMC: 1887720. DOI: 10.1084/jem.20030976. View

De Noronha S, Hardy S, Sinclair J, Blundell M, Strid J, Schulz O . Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein. Blood. 2004; 105(4):1590-7. DOI: 10.1182/blood-2004-06-2332. View

10.

Higgs H, Pollard T . Activation by Cdc42 and PIP(2) of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex. J Cell Biol. 2000; 150(6):1311-20. PMC: 2150692. DOI: 10.1083/jcb.150.6.1311. View

11.

Molina I, Sancho J, Terhorst C, Rosen F, Remold-ODonnell E . T cells of patients with the Wiskott-Aldrich syndrome have a restricted defect in proliferative responses. J Immunol. 1993; 151(8):4383-90. View

12.

Dupre L, Aiuti A, Trifari S, Martino S, Saracco P, Bordignon C . Wiskott-Aldrich syndrome protein regulates lipid raft dynamics during immunological synapse formation. Immunity. 2002; 17(2):157-66. DOI: 10.1016/s1074-7613(02)00360-6. View

13.

Humblet-Baron S, Sather B, Anover S, Becker-Herman S, Kasprowicz D, Khim S . Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest. 2007; 117(2):407-18. PMC: 1764857. DOI: 10.1172/JCI29539. View

14.

Sasahara Y, Rachid R, Byrne M, de la Fuente M, Abraham R, Ramesh N . Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Mol Cell. 2002; 10(6):1269-81. DOI: 10.1016/s1097-2765(02)00728-1. View

15.

Thrasher A . WASp in immune-system organization and function. Nat Rev Immunol. 2002; 2(9):635-46. DOI: 10.1038/nri884. View

16.

Anton I, de la Fuente M, Sims T, Freeman S, Ramesh N, Hartwig J . WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation. Immunity. 2002; 16(2):193-204. DOI: 10.1016/s1074-7613(02)00268-6. View

17.

Chellaiah M, Kuppuswamy D, Lasky L, Linder S . Phosphorylation of a Wiscott-Aldrich syndrome protein-associated signal complex is critical in osteoclast bone resorption. J Biol Chem. 2007; 282(13):10104-10116. DOI: 10.1074/jbc.M608957200. View

18.

Beel K, Cotter M, Blatny J, Bond J, Lucas G, Green F . A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene. Br J Haematol. 2008; 144(1):120-6. PMC: 3125974. DOI: 10.1111/j.1365-2141.2008.07416.x. View

19.

Locci M, Draghici E, Marangoni F, Bosticardo M, Catucci M, Aiuti A . The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function. J Exp Med. 2009; 206(4):735-42. PMC: 2715111. DOI: 10.1084/jem.20081773. View

20.

Torres E, Rosen M . Contingent phosphorylation/dephosphorylation provides a mechanism of molecular memory in WASP. Mol Cell. 2003; 11(5):1215-27. DOI: 10.1016/s1097-2765(03)00139-4. View