Donnelly, SK; (2013) Molecular dissection of a Nck:WIP:N-WASP signalling network. Doctoral thesis , UCL (University College London).

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Abstract

Nck and WASP/N-WASP play essential roles in the signalling networks that control Arp2/3 dependent actin polymerisation in a variety of contexts. These include functions downstream of the PDGF, Met and T cell receptors, in endocytosis and in the formation of invadopodia and podosomes. Vaccinia virus exploits a similar signalling network to enhance its cell-to-cell spread. During viral egress newly assembled virus particles fuse with the plasma membrane and activate Src and Abl family kinases. This leads to phosphorylation of a vaccinia protein, A36, and recruitment of a complex of Nck, Grb2, WIP and N-WASP, which activates the Arp2/3 complex to induce the polymerisation of actin tails. The aim of this thesis was to elucidate the exact role of WIP in Nck and N-WASP signalling and furthermore, to understand the connectivity and interplay between the proteins in this important and conserved signalling network. I found that WIP, or the related protein WIRE, is essential for the induction of actin tails during vaccinia virus infection. I determined that interactions of WIP with the second SH3 domain of Nck and the WH1 domain of N-WASP are crucial for Arp2/3 dependent actin polymerisation. Moreover, in the presence of WIP, the interaction of Nck and N-WASP is dispensable for the actin-based motility of vaccinia virus. Furthermore, in the absence of Grb2, the second SH3 domain of Nck is critical for actin tails formation. My data demonstrates that WIP forms an essential link between Nck and N-WASP that is required to promote Arp2/3 dependent actin polymerisation.

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