Role of WASP in cell polarity and podosome dynamics of myeloid cells.
Bottom Line: Podosome integrity and dynamics vary in response to changes in the physical and biochemical properties of the cell environment.In the current article we discuss the role of various factors in initiation and stability of podosomes and the roles of the Wiskott Aldrich Syndrome Protein (WASP) in this process.We discuss recent data indicating that in a cellular context WASP is crucial not only for localised actin polymerisation at the leading edge and in podosome cores but also for coordination of integrin clustering and activation during podosome formation and disassembly.
Affiliation: Randall Division of Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK.Show MeSH
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Mentions: WASP interacts at the amino terminus with the WASP Interacting Protein (WIP) (Anton et al., 2007; Ramesh et al., 1997). Like WASP, WIP is also an adapter protein that can interact with various other proteins involved in actin dynamics including WASP and the ubiquitous member of the same family N-WASP as well as cortactin, profilin and actin itself (Anton and Jones, 2006). Acting together WASP and WIP are crucial for the appropriate coordination between cell protrusion and integrin clustering into podosomes during myeloid cell migration. We have shown that WIP regulates the stability and localisation of WASP to podosomes (Chou et al., 2006). WIP DCs fail to form podosomes and like WASP DCs, assemble focal contacts instead. In the absence of WASP or WIP, DCs generate random protrusions at the cell margin that rapidly collapse back into the cell body. The focal contacts assembled by these cells allow firm adhesion onto the substratum but they are very stable (Chou et al., 2006; Calle et al., 2006b) and do not form and disassemble in coordination with the protrusion of the cell margin. Additionally, we and others have shown that in the absence of WIP, WASP is extensively degraded by the protease calpain and/or the proteosome (Chou et al., 2006; de la Fuente et al., 2007). However, upregulation of WASP in a WIP background by inhibiting the activity of calpain does not lead to reconstitution of podosomes. Instead, WASP localises into amorphous aggregates containing actin filaments and integrins organise forming focal contacts (Chou et al., 2006). Overall, our work suggests that WASP and WIP work as a functional unit involved in podosome initiation by coordinating actin polymerisation and integrin configuration. The presence of WASP and WIP in the podosome initiation complex is also supported by our observations using the monocytic cell line THP-1 differentiated into macrophage-like cells by treatment with TGFβ1 and plated on fibronectin. Live cell imaging of THP-1 cells co-expressing eGFP-WASP and WIP-mCherry shows that WASP and WIP are recruited simultaneously to nascent podosomes behind the extending lamellae (Fig. 5, Supplementary video 2).
Affiliation: Randall Division of Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK.