Michael Way

Introduction

Investigating exactly how pathogens hijack and subvert their unwilling hosts offers a unique opportunity.

Intracellular pathogens have developed numerous strategies to manipulate and use host cellular systems to facilitate their entry, replication, survival and spread.

Investigating exactly how pathogens hijack and subvert their unwilling hosts offers a unique opportunity to obtain mechanistic insights into the regulation and function of a multitude of cellular processes.

We use a combination of quantitative imaging and biochemical approaches to study vaccinia virus as a model system to interrogate the regulation and function of Src and Rho GTPase signalling networks, actin and microtubule-based transport as well as cell migration.

Outside the context of vaccinia infection, we also examine the mechanisms regulating the assembly and function of invadopodia as well as the cellular function of Tes, a tumour suppressor that regulates Mena-dependent cell migration.
 

Signalling networks and regulation of action polymerisation

The correct spatial and temporal regulation of actin polymerisation by phosphotyrosine-based signalling networks plays a critical role in many cellular processes. This includes cell migration, which plays an essential role during development and throughout the lifetime of multicellular organisms.

Unfortunately, deregulation of phosphotyrosine-based signalling networks can be devastating. For example if it stimulates tumour cells to undergo metastasis.

Understanding how phosphotyrosine-based signalling induces actin polymerisation involves identifying how specificity is generated and regulated within a network by a common set of domains with relatively modest binding affinities and multiple interaction partners.

This task is further complicated by the dynamic and co-operative nature of the interactions within any network. Consequently, unravelling exactly how signalling cascades stimulate actin polymerisation requires a molecular understanding and detailed knowledge of the interactions, dynamics and stoichiometry of proteins in the network.

The localised and sustained nature of the phosphotyrosine-based signalling network recruited by vaccinia make the virus an ideal model to tackle these fundamental questions and understand regulation of Arp2/3 dependent actin polymerisation (Weisswange et al., 2009; Nature. 458: 87-91).