Ivan De Curtis
Ivan De Curtis
affiliation: Università Vita-Salute San Raffaele
research area(s): Cell Biology, Neuroscience
Course: Cell and Molecular Biology
University/Istitution: Università Vita-Salute San Raffaele
2007-present, Professor in Biology, San Raffaele University, Milano.
1992-present, Group Leader, San Raffaele Scientific Institute, Milano
1988-1992, Postdoctoral fellow in molecular neurobiology, University of California, San Francisco.
1985-1988, Postdoctoral fellow in cell biology, European Molecular Biology Laboratory, Heidelberg.
1987, Ph.D. in Cellular and Molecular Biology, University of Milano.
Cell motility is involved in a diversity of physiological and pathological events, and requires molecular networks to coordinate adhesive, trafficking, and cytoskeletal processes. Our aim is to identify and characterize molecular networks that are functionally linked to Rho and Arf family GTPases, important regulators of cell motility. In this direction we have identified the GIT1/p95-APP1 protein that is part of multi-molecular complexes interacting with activated Rac GTPases. GIT1 is an ArfGAP that interacts with regulators of Rac and of integrin-mediated adhesion. Using cell lines and primary neurons we found that GIT1 regulates the protrusive activity of moving cells, and represents an important link between adhesion, actin dynamics, and membrane traffic during migration. We have uncovered a mechanism for the regulation of GIT1 function based on the release of an intramolecular interaction that keeps the protein inactive, and found that the GIT1-interacting protein liprin-alpha is an essential regulator of cell edge dynamics, migration, and tumor cell invasion. We are now further analyzing the mechanisms by which GIT and Liprin proteins regulate migration and neuronal development. Another aspect of our research is the analysis of Rac function during the development of the nervous system. We have produced knockout mice for the neural-specific Rac3 GTPase, conditional knockout for the deletion of Rac1 in neurons, and double knockout mice for both Rac genes. While deletion of either Rac causes milder developmental defects, deletion of both genes causes severe neurological and developmental brain defects. Rac1 and Rac3 cooperate for normal neuronal development, and our current research is aiming at the identification of the role of Rac and associated proteins in the observed defects, both in cultured neurons and in vivo, with particular attention to late neuronal development and synaptogenesis. The results also indicate that Rac KO mice represent interesting models to study mental diseases.
Asperti C, Astro V, Pettinato E, Paris S, Bachi A, de Curtis I. (2011) Biochemical and Functional Characterization of the Interaction between Liprin-a1 and GIT1: Implications for the Regulation of Cell Motility. PLoS One 6, e20757.

Basso V, Corbetta S, Gualdoni S, Tonoli D, Poliani PL, Sanvito F, Doglioni C, Mondino A, de Curtis I. (2011) Absence of Rac1 and Rac3 GTPases in the nervous system hinders thymic, splenic and immune-competence development. Eur. J. Immunol. 41, 1410-1419.

de Curtis I. (2011) Host-pathogen interactions: cheating the host by making new connections. Curr. Biol. 21: R192-194.

Astro V, Asperti C, Cangi MG, Doglioni C, de Curtis I. (2011) Liprin-a1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation. Oncogene 30, 1841-1849.

de Curtis I. (2011) Function of liprins in cell motility. Exp. Cell Res. 317, 1-8.

Asperti C, Pettinato E, de Curtis I. (2010) Liprin-alpha1 affects the distribution of low-affinity beta1 integrins and stabilizes their permanence at the cell surface. Exp. Cell Res. 316, 915-926.

Asperti C, Astro V, Totaro A, Paris S, de Curtis I. (2009) Liprin-alpha1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins. J. Cell Sci. 122, 3225-3232.

Corbetta S, Gualdoni S, Ciceri G, Monari M, Zuccaro E, Tybulewicz VL, de Curtis I. (2009) Essential role of Rac1 and Rac3 GTPases in neuronal development. FASEB J. 23, 1347-1357.

Totaro A., Paris S., Asperti C., de Curtis I. (2007) Identification of an intramolecular interaction important for the regulation of GIT1 functions. Mol. Biol. Cell 18:5124-5138.

Za L., Albertinazzi C., Paris S., Gagliani M., Tacchetti C., de Curtis I. (2006) bPIX controls cell motility and neurite extension by regulating the distribution of GIT1. J. Cell Sci. 119:2654-2666.

Corbetta, S., Gualdoni, S., Albertinazzi, C., Paris, S., Croci, L., Consalez, G. G., and de Curtis, I. (2005) Generation and characterization of Rac3 knockout mice. Mol. Cell Biol. 25, 5763-5776.

Albertinazzi, C., Za, L., Paris, S., and de Curtis, I. (2003) Arf6 and a functional PIX/p95-APP1 complex are required for Rac1B-mediated neurite outgrowth. Mol. Biol. Cell, 14, 1295-1307.

de Curtis I. (2001) Cell migration: GAPs between membrane traffic and the cytoskeleton. EMBO Reports, 2, 277-281

Di Cesare, A., Paris, S., Albertinazzi, C. Dariozzi, S., Andersen, J., Mann, M., Longhi, R. and de Curtis, I. (2000) p95-APP1 links membrane transport to Rac-mediated reorganization of actin. Nature Cell Biol., 2, 521-530
Project Title:
Mechanisms for the regulation of Rac-mediated cell migration.
Cell motility is central to several physiological and pathological events. Cell migration is mediated by the Rac GTPases that affect the dynamics of actin at the front of moving cells. We are interested in the characterization of new mechanisms that regulate Rac-mediated migration, and in particular the dynamic protrusive events that affect the cell edge during normal and tumor cell motility. In this direction, we have identified a molecular network that regulate adhesion and cell edge dynamics during migration. This network includes the GIT/PIX complex isolated by affinity chromatography on Rac GTPases, and the liprin-α1 adaptor protein, a novel regulator of integrin-mediated migration highly expressed in human tumors. Overexpression and silencing experiments have shown an essential role of liprin-α in the control of migration and invasion, and in the dynamics and turnover of focal adhesions at the cell edge. A project is available to analyze the mechanisms by which liprin-α and GIT/PIX proteins regulate migration. The project includes the identification and characterization of new players functionally interacting with the liprin-α/GIT/PIX network; the identification of mechanisms linking the localization of liprin-α at the plasma membrane with its positive effects on cell migration; the functional analysis of the identified proteins by different cell motility assays performed in 2D and 3D environments; the dynamic analysis of the cellular events regulated by these proteins by time-lapse video-imaging. The results from this project will advance our understanding of fundamental regulatory mechanisms and identify new targets for cancer therapy.

Project Title:
Molecular mechanisms regulating tumor cell invasion.
Invasion requires modifications in tumor cell motility. This PhD project is based on our recent findings that liprin-α1 is a new player in the regulation of tumor cell invasion. Liprin-α1 is an adaptor protein amplified and highly expressed in different human cancers. We have shown that liprin-α1 is required for invasion in vitro by highly metastatic carcinoma cells. Time-lapse analysis demonstrated that liprin-α1 regulates tumor cell motility by affecting the stability of lamellipodia and invadopodia, both required for invasion. In particular, liprin-α1 levels influence the degradative activity of invadopodia. One aim of the project is to investigate the machinery underlying the positive effects of liprin-α1 on invasion. Candidate liprin partners will be tested for their implication in the regulation of invasion by in vitro invasion assays. Time-lapse imaging will be used to study the effects of the proteins examined on dynamic processes required for invasion. Biochemical analysis will help identifying differences between tumor cells with distinct invasive potentials. The second aim of the project is to investigate the function of liprin-α1 by using in vivo mice models. Stable cell lines in which the protein of interest has been either downregulated or overexpressed will be utilized for injection into animals to study their effects on the formation and development of tumors and metastases. The results from this project will expand the knowledge on the mechanisms that influence the invasive behavior of malignant tumor cells, and will highlight new possible targets for prognosis and therapeutic intervention.