Signals are the language of life, mediating the communication essential for cells’ proper behavior. Within cells, intricate networks of proteins transduce signals into the appropriate physiological response, and many diseases are caused by malfunctioning of these signal transduction networks. Our interest is in the mechanisms through which integrins, Rho/Rac GTPases and caveolin cooperate to regulate gene expression, cell cycle progression, migration, polarization, vesicle trafficking and epithelial-mesenchymal transition (EMT), key processes in the pathogenesis of cancer and inflammatory and cardiovascular diseases.
Integrins (the main ECM receptors) regulate caveolinmediated endocytosis of Rac binding sites within cholesterolenriched membrane microdomains (CEMM). Our recent work shows that cells lacking caveolin exit quiescence and progress through the cell cycle faster than wild-type cells, and are able to proliferate without anchorage to substrate and do not show the normal downregulation of cyclin D1 upon serum deprivation or detachment. Surprisingly, this proliferative advantage is independent of Erk–MAPK, being instead driven by increased membrane order and Rac membrane targeting. We are currently assessing the contribution of this mechanism to atherogenesis.
A related interest is the influence of caveolin on cell polarity and directional migration. Caveolin regulates these processes in 2D, through coordination of Src kinase and Rho GTPase signaling. We are investigating how this regulation operates in 3D, focusing on the contribution of caveolin to 3D microenvironment remodeling.
To understand the molecular mechanisms by which integrins regulate caveolin trafficking, we are studying actin polymerization pathways that control caveolae dynamics, and we are also conducting an RNAi-based genome-wide highcontent image analysis screen in collaboration with the Cellomics Unit.
Our work on EMT has identified a role for ERK/NF-kB/Snail1 signaling, and we are currently studying signaling pathways underlying EMT and fibrosis during chronic peritoneal inflammation.
Figure legend: Mouse Embryo Fibroblasts (MEFs) monolayers where scraped to create wounds and stimulate directional migration. Absence of Caveolin-1 expression in MEFs correlates with decreased directionality of cell migration, decreased polarization and increased plasma membrane targeting of the small GTPase Rac
- Miguel A. del Pozo
- Group leader
- Ext.1158
Miguel Ángel del Pozo graduated in Medicine and Surgery at the Universidad de Valladolid in 1991, and then pursued a research career while specialising in Immunology at the Hospital de la Princesa in Madrid (1995). The subject of his PhD thesis (Department of Biochemistry, UAM, 1997) was the function of adhesion receptors and chemokines in cell polarisation and leukocyte migration in inflammation. During his postdoc tenure in the laboratory of Martin Schwartz (The Scripps Research Institute, La Jolla, California, 1998-2002) he contributed to elucidate the role of Rho-family GTPases in the regulation of intracellular signals by integrins, growth factors and mechanical stimuli. He later started his own group as Assistant Professor at Scripps, focusing on integrin signalling and plasma membrane heterogeneity in anchorage-dependent growth. He moved to CNIC as Junior Group Leader in 2004. At CNIC he studies the role of integrins, caveolin and Rho/Rac GTPases in membrane trafficking, cell migration and cell growth. In 2004 he received the EURYI (European Young Investigator) Award in Biomedicine, and in 2005 was elected by EMBO as member of the Young Investigator Programme (EMBO YIP). He gained an “Investigador Científico” (Senior Tenured Scientist) position at the CSIC in 2005. Since 2006 Del Pozo is Senior Group Leader at CNIC (level I), and since January 2007 he is Acting as Head of the Vascular Biology and Inflammation Department. In 2007 the SEBBM (Spanish Association for Biochemistry and Molecular Biology) awarded him the Beckman Coulter distinction, for under-40 researchers.
© 2012 Centro Nacional de Investigaciones Cardiovasculares