ICASADEG · Identification of Caveolin Sequences involved in Anchorage-dependence of cell growth
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-10-01 → 2007-09-30
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
Lines connect the coordinator with its partners. CORDIS does not always give exact coordinates for projects before 2014. These points are placed at city or country level.
Results in brief
Final Activity Report Summary - ICASADEG (Identification of Caveolin Sequences involved in Anchorage-dependence of cell growth)
Development, angiogenesis, wound healing and metastasis all involve the movement of cells in response to changes in the extra-cellular environment. Cell migration and polarization are key biological processes, and both are critically regulated by two families of proteins: Integrins and small GTPases of the Rho/Rac family. Our research focuses on identifying molecular mechanisms by which they regulate migration and polarisation. Integrins regulate membrane targeting of Rac/Rho family GTPases (Del Pozo et al, EMBO J 2000, Nature Cell Biol 2002), and this is mediated by cholesterol-enriched membrane microdomains (CEMM) also named lipid rafts (Del Pozo et al, Science 2004). Internalisation of Rac binding sites in CEMM is mediated by caveolin-1 (Del Pozo et al, Nature Cell Biol 2005). Caveolin-1 inhibits anchorage-independent cell growth (AIG) and is a candidate tumour suppressor, although the mechanism(s) by which this crucial function is exerted remain(s) obscure. By sequestering phosphorylated caveolin in focal adhesions (FA), integrins inhibit CEMM endocytosis, which occurs upon its recruitment to caveolae. These results may provide a molecular explanation for the role of caveolin-1 as tumour suppressor. The localisation of caveolin phosphorylated on Tyr-14 (pYcav) at Focal Adhesions (FA) is intriguing and suggests that this protein could have an impact in regulating FA dynamics. We have recently demonstrated a role for caveolin-1 in the establishment of cell polarity and directional migration, both intrinsic persistency and the response to external chemotactic cues (Grande-García et al, J Cell Biol , 2007). To determine whether caveolin-1 plays a role in cell migration, we have used fibroblasts from knockout mice. Caveolin-1 deficient cells lose normal cell polarity, exhibit impaired wound healing and have decreased Rho and increased Rac and Cdc42 GTPase activities. Directional persistency of migration is lost and the cells show an impaired response to external directional stimuli. Both Src inactivation and p190RhoGAP knockdown restore the wild-type phenotype to caveolin-1 deficient cells, suggesting that caveolin-1 stimulates normal Rho-GTP loading through inactivation of the Src/p190RhoGAP pathway. These findings highlight the importance of caveolin-1 in the establishment of cell polarity during directional migration through coordination of Src kinase and Rho GTPases signalling. These ex-vivo findings support the altered phenotype observed in vivo in processes such as angiongenesis and dermal wound repair, which is deficient in Cav-1 deficient mice (Grande-García et al, J Cell Biol , 2007).
Data: CORDIS, © European Union
Project objective
Integrins are key regulators of gene expression, cell proliferation and migration. Alteration of these processes is central to tumourigenesis. Integrin signals mediate anchorage-dependence of cell growth, while growth of cancer cells is anchorage-independent. Integrins regulate membrane targeting of Rac and Cdc42, also involved in oncogenesis. Integrin-regulated Rac binding sites are in lipid rafts (membrane domains enriched in cholesterol and glycosphingolipids).Internalisation of Rac binding sites is mediated by caveolin-1, a structural component of a subtype of rafts termed caveolae. Caveolin-1 regulates anchorage-dependent growth and is a tumour suppressor. Integrin-mediated retention of phosphorylated caveolin in focal adhesions inhibits raft internalisation, which occurs upon its recruitment to caveolae after cell detachment. These results may provide a molecular explanation for the role of caveolin-1 as tumour suppressor and provide insight into the mechanism of anchorage-independent growth, one of the hallmarks of cancer.The main goal of this research proposal is to study the relevance of this novel mechanism to cancer. This specific project aims to identify sequences within caveolin involved in regulation of raft internalisation, cell cycle progression and anchorage-dependent cell growth. Caveolin sporadic mutations occurring in human cancers will be tested for these effects. This objective integrates into a bigger project that also aims to identify molecular mechanisms by which caveolin regulates anchorage-dependent signalling pathways and cell cycle progression and to identify oncogenes that induce constitutive surface localization of rafts (and hence Rac), and/or changes in phosphocaveolin localization.These studies will contribute to a better understanding of adhesion-dependent signalling and anchorage-dependence of cell growth, and therefore to the pathogenesis of the malignant disease. They will also help in identifying targets for cancer therapy.
Original text from CORDIS.
Participants
- FUNDACIÓN CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III · MADRIDCoordinatorCity levelSpain
Links
Data: CORDIS, © European Union