Research Theme within School of Biosciences: Molecular and Cell Biology
The role of Rho family GTPases in regulation of cell function
Throughout the life of an organism cells must 'sample' their environment and take decisions accordingly. Cellular interactions with extracellular matrix proteins such as fibronectin, via integrin adhesion receptors, play an essential role in both developing and adult organisms. Many cellular functions require the integration of adhesion mediated signals with those received via growth factor receptors. Identifying the nature of these signals and the mechanism by which they are integrated is clearly essential to the understanding of how normal cellular function is regulated.
The Rho family of small GTP-binding proteins regulate both cell adhesion and growth factor mediated signal transduction. As such, they are believed to play a pivotal role in integration of adhesion and growth factor dependent signals. The main focus of our research is directed towards understanding how Rho family proteins regulate adhesion-mediated signal transduction events.
1. Regulation of Epithelial Cell Function by RhoFamily GTPases
Normal epithelial cell function is dependent on both cell-cell interactions mediatedby cadherin adhesion receptors and interaction with extracellular matrix proteins via integrin adhesion receptors. There is good evidence that both of these adhesion events are regulated by members of the Rho family of small GTP-binding proteins. We are particularly interested in the role played by Rho-family members in regulating integrin-dependent signalling events in human epidermal keratinocytes.
2. The Role of Syntenin-1 in Trafficking of Frizzled Receptors in Breast Cancer
Frizzled (Fz) receptors are a group of seven-pass transmembrane receptors that play a key role in the transduction of signalsfrom secreted ligands known as Wnts. Wnt signaling plays a central role indevelopment, regulating proliferation, stem cell maintenance and cell fate decisions, as well as coordinating cell movements and the establishment of tissue polarity. Deregulated Wnt signaling is also a major contributing factor to epithelial carcinogenesis, including breast and colon cancer. Syntenin-1 is a membrane-associated adapter protein that we, and others, have shown interacts with a number of transmembrane and cytosolic proteins.
One of the main functions of syntenin-1 is the traffickingof membrane receptors to and from the plasma membrane. Increased expression of syntenin-1 is also associated with invasive behaviour in a number of breast cancer cell lines. In collaboration with Fedor Berditchevski and Chris Tselepis we are using a combination of biochemistry and cell biology to analysethe role of syntenin-1 in post-endocytic trafficking of Frizzled receptors inbreast cancer cells.
3. The role of Rho GTPases in Glioblastoma
Glioblastoma is a common and aggressive brain tumour which is generally resistant to currently used therapies. In collaboration with Francesco Falciani and Roy Bicknell we are using a combination of bioinformatics and cell biology to analyse the role of Rho family GTPases in the development and spread of this tumour.
Hotchin NA, Cover TL and Akhtar N (2000). Cell vacuolation induced by the VacA cytotoxin of Helicobacter pylori is regulated by the Rac1 GTPase. J. Biol. Chem. 275, 14009-14012.
Akhtar N and Hotchin NA (2001). RAC1 regulates adherens junctions through endocytosis of E-cadherin. Mol. Biol. Cell 12, 847-862.
Sawada S,Yoshimoto M, Odintsova E, Hotchin NA and Berditchevski F (2003). The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras. J. Biol. Chem. 278, 26323-26326.
McMullanR, Lax S, Robertson VH, Radford DR, Broad S, Watt FM, Rowles A, Croft DR, OlsonMF and Hotchin NA (2003). Keratinocyte differentiation is regulated by the Rho and ROCK signaling pathway. Curr. Biol.13, 2185-2189.
Turner FE, Broad S, Khanim FL, Jeanes A, Talma S, Hughes S, Tselepis C, Hotchin NA (2006). Slug regulates integrin expression and cell proliferation in humanepidermal keratinocytes. J. Biol. Chem. 281, 21321-21331.
Latysheva N, Muratov G, Rajesh S, Padgett M, Hotchin NA, Overduin M, Berditchevski F (2006). Syntenin-1 is a new component of tetraspanin-enriched microdomains:mechanisms and consequences of the interaction of syntenin-1 with CD63. Mol.Cell Biol. 20, 7707-7718.
Brookes MJ, Boult J, Roberts K, Cooper BT, Hotchin NA, Matthews G, Iqbal T, Tselepis C (2008). A role for iron in Wnt signaling. Oncogene 27, 966-975.
Lock FE and Hotchin NA (2009). Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS ONE 4, e8190.
Lim J, Hotchin NA, Caron E (2011). Ser756 of β2 integrin controls Rap1 activity during inside-out activation of αMβ2. Biochem. J. 437, 461-467.
Lock FE, Ryan KR, Poulter NS, Parsons M, Hotchin NA (2012) Differential Regulation of Adhesion Complex Turnover by ROCK1 and ROCK2. PLoS ONE 7, e31423.
Ryan KR, Lock FE, Heath JK, Hotchin NA. (2012). Plakoglobin-dependent regulation of keratinocyte apoptosis by Rnd3. J. Cell Sci. 125, 3202-3209.
Lim J and Hotchin NA (2012). Signalling mechanisms of the leukocyte integrin aMb2: Current and future perspectives. Biol. Cell doi: 10.1111/boc.201200013.
Scales TM, Jayo A, Obara B, Holt MR, Hotchin NA, Berditchevski F and Parsons M (2012). a3b1 integrins regulate CD151 complex assembly and membrane dynamics in carcinoma cells within 3D environments. Oncogene doi:10.1038/onc.2012.415.