SCHOOL OF BIOCHEMISTRY
Research
Research groups
Research groups
Mark Bass
Research Fellow
+44 (0)117 33 12182 (tel)
+44 (0)117 33 12168 (fax)
mark.bass@bristol.ac.uk
Research
How is cell migration regulated by the extracellular matrix: role of syndecan-4 in the regulation of Rho family GTPases?
In healthy adults, the majority of cells lie dormant. Cell adhesion is tightly regulated so that proliferation and migration only occur when cells are stimulated by infection or wounding. Resolving the mechanisms by which individual cells recognise and respond to tissue damage is critical to the development of strategies to improve wound healing and prevent scarring in patients. Syndecan-4 has emerged as the transmembrane receptor responsible for recognition of changes extracellular matrix and has become the focus of my laboratory. We are interested in studying the role of syndecan-4 on three different levels.
- We are examining the regulation of protrusive (Rac1) and contractile (RhoA) signalling molecules by syndecan-4. Spatial and temporal coordination of protrusive and contractile signals are central to the process of cell migration, so we are combining traditional biochemistry with live cell imaging and FRET-based analysis to define this relationship. Perturbation of components of the syndecan-4 signalling chain by RNAi is revealing that syndecan-4 synchronises the activation/inhibition of antagonistic signals, and is responsible for localised membrane protrusion at the cell’s leading edge.
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To follow how the molecular changes affect cell behaviour, we are using atomic force microscopy to measure directly, the changes in adhesion dynamics and strengthening upon syndecan-4 engagement. We are then using nano-engineered surfaces to control the distribution of extracellular matrix and test the response of cells to spatially restricted cues.
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The challenge is to use our biological findings to develop therapeutic strategies that will affect patient treatment. We have begun to use our understanding of syndecan-4 biology to probe, at the cellular level, the mechanism of action of novel therapeutic agents that can already reduce healing times in patients by 40%. A close collaboration with pharmaceutical companies will ensure that our lab-based cell biology will have a direct impact on patient care within 10 years.
The use of FRET probes and imunofluorescence reveals that, as cells integrate with a fibrillar matrix (A), Rac1 activity (B) and RhoA suppressors (C) are localised to the leading edge of the cell. Rac1 activation is triggered by engagement of syndecan-4 (D) and can be mimicked by the application of therapeutic agents such as pulsed ultrasound (E). The directionality of cell migration in 3D (black bars), but not 2D (grey bars) is determined by the relationship between syndecan-1 and Rac1 (F). Likewise, engagement of syndecan-4 directs the migration paths of cells over nano-engineered substrates (G).
Group
Roz WilliamsonRecent publications
Humphries JD, Byron A, Bass MD, Craig SE, Pinney JW, Knight D, Humphries MJ. (2009) Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Science Signaling. 2: ra51.
Mahoney CM, Morgan MR, Harrison A, Humphries MJ, Bass MD. (2009) Therapeutic ultrasound bypasses canonical syndecan-4 signaling to activate Rac1. J Biol Chem. 284:8898-909.
Bass MD, Morgan MR, Roach KA, Settleman J, Goryachev AB, Humphries MJ. (2008) p190RhoGAP is the convergence point of adhesion signals from a5ß1 integrin and syndecan-4. J Cell Biol. 181:1013-26.
Bass MD, Roach KA, Morgan MR, Mostafavi-Pour Z, Schoen T, Muramatsu T, Mayer U, Ballestrem C, Spatz JP, Humphries MJ. (2007) Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix. J Cell Biol. 177:527-38.