Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages.

Podosomes are integrin-containing adhesion structures commonly found in migrating leukocytes of the monocytic lineage. The actin cytoskeletal organisation of podosomes is based on a WASP- and Arp2/3-mediated mechanism. WASP also associates with a second protein, WIP (also known as WIPF1), and they co-localise in podosome cores. Here, we report for the first time that WIP can be phosphorylated on tyrosine residues and that tyrosine phosphorylation of WIP is a trigger for release of WASP from the WIP-WASP complex. Using a knockdown approach together with expression of WIP phosphomimics, we show that in the absence of WIP-WASP binding, cellular WASP is rapidly degraded, leading to disruption of podosomes and a failure of cells to degrade an underlying matrix. In the absence of tyrosine phosphorylation, the WIP-WASP complex remains intact and podosome lifetimes are extended. A screen of candidate kinases and inhibitor-based assays identified Bruton's tyrosine kinase (Btk) as a regulator of WIP tyrosine phosphorylation. We conclude that tyrosine phosphorylation of WIP is a crucial regulator of WASP stability and function as an actin-nucleation-promoting factor.

Vijayakumar V ，Monypenny J ，Chen XJ ，Machesky LM ，Lilla S ，Thrasher AJ ，Antón IM ，Calle Y ，Jones GE ... -  《-》

Requirement for a complex of Wiskott-Aldrich syndrome protein (WASP) with WASP interacting protein in podosome formation in macrophages.

Tsuboi S 《JOURNAL OF IMMUNOLOGY》

WIP regulates the stability and localization of WASP to podosomes in migrating dendritic cells.

Chou HC ，Antón IM ，Holt MR ，Curcio C ，Lanzardo S ，Worth A ，Burns S ，Thrasher AJ ，Jones GE ，Calle Y ... -  《-》

WASP-interacting protein (WIP): working in polymerisation and much more.

Antón IM ，Jones GE ，Wandosell F ，Geha R ，Ramesh N ... -  《-》

WIP: WASP-interacting proteins at invadopodia and podosomes.

Regulated cell invasion resulting from migratory and matrix-degrading events is an essential step in physiological processes such as the inflammatory response and tissue repair. Cell invasion is also thought to be a critical parameter in pathological conditions such as cancer metastasis. The migration of normal and cancer cells is largely driven by the actin cytoskeleton, which controls cell shape, adhesion and contractility. Podosomes and invadopodia are actin-rich protrusions that drive invasion in normal and cancer cells. These structures protrude from the basal region of the cell facing the extracellular matrix, where they adhere to and degrade the matrix, thus facilitating invasive migration. WASP (Wiskott-Aldrich syndrome protein) and WIP (WASP-interacting protein) localise to the actin rich core of podosomes and play a critical role in their formation. More recently, studies performed on microarray data sets from cancer patients of several tumour categories show a strong correlation between reduced WIP expression and improved prognosis. In this article, we identify endogenous WIP at the distal tips of cancer cell invasive protrusions and we summarise recent advances in the study of the roles of WIP- and WASP-protein families during migration and invasion of normal and cancer cells related to podosome and invadopodium generation.

García E ，Jones GE ，Machesky LM ，Antón IM ... -  《-》