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

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

doi:10.1073/pnas.0904346106

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

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

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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.

Original language	English
Pages (from-to)	15738 - 15743
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	106
Issue number	37
DOIs	https://doi.org/10.1073/pnas.0904346106
Publication status	Published - 15 Sept 2009

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Blundell, M. P., Bouma, G., Metelo, J., Worth, A., Calle, Y., Cowell, L. A., Westerberg, L. S., Moulding, D. A., Mirando, S., Kinnon, C., Cory, G. O., Jones, G. E., Snapper, S. B., Burns, S. O., & Thrasher, A. J. (2009). Phosphorylation of WASp is a key regulator of activity and stability in vivo. Proceedings of the National Academy of Sciences of the United States of America, 106(37), 15738 - 15743. https://doi.org/10.1073/pnas.0904346106

@article{ae36fff7035e44b7b4fda92ecfcef92d,

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.",

author = "Blundell, {Michael P.} and Gerben Bouma and Joao Metelo and Austen Worth and Yolanda Calle and Cowell, {Lucy A.} and Westerberg, {Lisa S.} and Moulding, {Dale A.} and Samuel Mirando and Christine Kinnon and Cory, {Giles O.} and Jones, {Gareth E.} and Snapper, {Scott B.} and Burns, {Siobhan O.} and Thrasher, {Adrian J.}",

year = "2009",

month = sep,

day = "15",

doi = "10.1073/pnas.0904346106",

language = "English",

volume = "106",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "1091-6490",

publisher = "National Acad Sciences",

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Blundell, MP, Bouma, G, Metelo, J, Worth, A, Calle, Y, Cowell, LA, Westerberg, LS, Moulding, DA, Mirando, S, Kinnon, C, Cory, GO, Jones, GE, Snapper, SB, Burns, SO & Thrasher, AJ 2009, 'Phosphorylation of WASp is a key regulator of activity and stability in vivo', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 37, pp. 15738 - 15743. https://doi.org/10.1073/pnas.0904346106

TY - JOUR

T1 - Phosphorylation of WASp is a key regulator of activity and stability in vivo

AU - Blundell, Michael P.

AU - Bouma, Gerben

AU - Metelo, Joao

AU - Worth, Austen

AU - Calle, Yolanda

AU - Cowell, Lucy A.

AU - Westerberg, Lisa S.

AU - Moulding, Dale A.

AU - Mirando, Samuel

AU - Kinnon, Christine

AU - Cory, Giles O.

AU - Jones, Gareth E.

AU - Snapper, Scott B.

AU - Burns, Siobhan O.

AU - Thrasher, Adrian J.

PY - 2009/9/15

Y1 - 2009/9/15

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.0904346106

DO - 10.1073/pnas.0904346106

M3 - Article

SN - 1091-6490

VL - 106

SP - 15738

EP - 15743

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 37

ER -

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

Abstract

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