Unknown

Dataset Information

0

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.

SUBMITTER: Blundell MP 

PROVIDER: S-EPMC2736139 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

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

Blundell Michael P MP   Bouma Gerben G   Metelo Joao J   Worth Austen A   Calle Yolanda Y   Cowell Lucy A LA   Westerberg Lisa S LS   Moulding Dale A DA   Mirando Samuel S   Kinnon Christine C   Cory Giles O GO   Jones Gareth E GE   Snapper Scott B SB   Burns Siobhan O SO   Thrasher Adrian J AJ  

Proceedings of the National Academy of Sciences of the United States of America 20090901 37

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-polyme  ...[more]