Professor Martin Humphries
Cell Adhesion Signalling
The fundamental importance of cell-extracellular matrix (ECM) adhesion for multicellular life has been established by a combination of genetic and pharmacological analyses. Studies in model organisms have demonstrated that interactions between ECM assemblies and their cell surface receptors (primarily integrins and syndecans) provide physical support for tissues and a platform for directed migration. In patients with inflammatory, neoplastic and infectious diseases, aberrant adhesion perturbs cellular trafficking and causes dysregulation of cellular differentiation. Within the last decade, the first generation of rationally designed, anti-adhesive drugs has been approved for human therapy.
Adhesion receptor function is partly determined by an ability to tether the contractile cytoskeleton to the plasma membrane, but there is also evidence that integrins and syndecans modulate signalling events that are essential for cellular differentiation. Most notably, these receptors organise signalling complexes at specialised cell adhesion contacts to modulate differentiation and cell fate, provide support for cells in order to maintain cohesion, and permit the generation of traction forces to enable movement. Cell adhesion alters the fluxes of virtually all signalling pathways, including the Rho family of small GTPases, which play a central role in controlling actin polymerisation, cytoskeletal targeting and adhesion contact assembly.
Over the past five years, our research has emphasised cell biological and biochemical analyses of adhesion signalling. We now aim to move this work to a new level and determine the molecular basis of adhesion signalling at the proteomic level. In this context, we have recently developed a technique to isolate, document and quantify transmembrane receptor-associated signalling complexes [Science Sig. (2009) 2: ra51]. The availability of this workflow now permits targeted proteomic analyses of adhesion signalling. Our long-term aim is to understand how adhesion receptors interpret the cellular microenvironment to control cellular phenotype, and in the next five years, towards this goal, we aim to answer three questions of high
importance for adhesion receptor function:
1. How are adhesion receptor signalling networks organised?
2. How does the conformation of active and inactive integrins regulate signalling complex assembly?
3. How does microenvironmental sensing by adhesion receptors control cell phenotype?
These studies combine isolation of adhesion receptor-associated complexes with proteomic analyses by mass spectrometry, and are being followed up with bioinformatic analyses of large datasets, biochemical and molecular biological analyses of signalling pathways, and immunofluorescence studies of adhesion complex components in a range of cell types including fibroblasts, embryonic and mesenchymal stem cells, invasive cancer cells, and mammary epithelial cells.