Cell motility is necessary for physiological events such as the wiring of the nervous system, as well as for pathological conditions like tumor cell invasion. Cell motility is regulated by molecular networks that allow the coordination of adhesion, cytoskeletal organization, and molecular trafficking at the leading edge of motile cells.
We are interested in the characterization of the mechanisms driving the protrusive activity at the edge of migrating cells and developing neurons. We are characterizing the function of a protein network implicated in the regulation of protrusion in distinct settings, such as cell migration, invasion, and neuronal development. This network includes a core of scaffold proteins that interacts with regulatory enzymes (small GTPases, kinases, phosphatases), to localize them at specific sites of the migrating cell to regulate protrusion. The network under study forms plasma membrane-associated platforms (PMAPs) that specifically assemble near the front of migrating cells. High resolution imaging in living cells shows that PMAPs are dynamic. They are made of protein condensates that show liquid-like behavior. The study of protein condensates with liquid behavior is an exciting developing area of research, since they underlie the organization of several physiological and pathological processes in living organisms.
Our studies indicate that PMAPs are condensates essential to regulate protrusion during cell motility. To address their function, we combine biochemical-structural analysis, with high resolution imaging to follow dynamic molecular events in living cells, and quantitative assays to address their effects on cell motility in vitro and in vivo. Our working model is that the liquid-like properties of PMAPs are important to recruit relevant proteins at specific sites and times in cells to regulate their behavior. The understanding of the mechanisms regulating assembly and disassembly of PMAPs is expected to highlight molecular players relevant to cell invasion and neuronal development.
Ramella M, Ribolla LM, de Curtis I. Liquid-Liquid Phase Separation at the Plasma Membrane-Cytosol Interface: Common Players in Adhesion, Motility, and Synaptic Function. J Mol Biol. (2022) 434:167228.
de Curtis I. Biomolecular Condensates at the Front: Cell Migration Meets Phase Separation.Trends Cell Biol. (2021) 3:145-148.
Pehkonen H, de Curtis I, Monni O. Liprins in oncogenic signaling and cancer cell adhesion. Oncogene. (2021) 40:6406-6416.
Sala K, Corbetta A, Minici C, Tonoli D, Murray DH, Cammarota E, Ribolla L, Ramella M, Fesce R, Mazza D, Degano M, de Curtis I. The ERC1 scaffold protein implicated in cell motility drives the assembly of a liquid phase. Sci Rep. (2019) 9:13530.
de Curtis I. The Rac3 GTPase in Neuronal Development, Neurodevelopmental Disorders, and Cancer. Cells. (2019) 8:1063.
Sala K, Raimondi A, Tonoli D, Tacchetti C, de Curtis I. Identification of a membrane-less compartment regulating invadosome function and motility. Sci Rep. (2018) 8:1164.
Franchi SA, Astro V, Macco R, Tonoli D, Barnier JV, Botta M, de Curtis I. Identification of a Protein Network Driving Neuritogenesis of MGE-Derived GABAergic Interneurons. Front Cell Neurosci. (2016) 10:289.
Astro V, Tonoli D, Chiaretti S, Badanai S, Sala K, Zerial M, de Curtis I. Liprin-α1 and ERC1 control cell edge dynamics by promoting focal adhesion turnover. Sci Rep. (2016) 6:33653.
Pennucci R, Talpo F, Astro V, Montinaro V, Morè L, Cursi M, Castoldi V, Chiaretti S, Bianchi V, Marenna S, Cambiaghi M, Tonoli D, Leocani L, Biella G, D'Adamo P, de Curtis I. Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks. Cereb Cortex. (2016) 26:873-890.
Astro V, de Curtis I. Plasma membrane-associated platforms: dynamic scaffolds that organize membrane-associated events. Science Signal. (2015) 8(367):re1.
Vaghi V, Pennucci R, Talpo F, Corbetta S, Montinaro V, Barone C, Croci L, Spaiardi P, Consalez GG, Biella G, de Curtis I. Rac1 and Rac3 GTPases Control Synergistically the Development of Cortical and Hippocampal GABAergic Interneurons. Cereb Cortex. (2014) 24:1247-58.
Astro V, Asperti C, Cangi MG, Doglioni C, de Curtis I. Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation. Oncogene (2011) 30:1841-9.
Corbetta S, Gualdoni S, Ciceri G, Monari M, Zuccaro E, Tybulewicz VL, de Curtis I. Essential role of Rac1 and Rac3 GTPases in neuronal development. FASEB J. (2009) 23:1347-57.
Di Cesare A, Paris S, Albertinazzi C, Dariozzi S, Andersen J, Mann M, Longhi R, de Curtis I. p95-APP1 links membrane transport to Rac-mediated reorganization of actin. Nature Cell Biol. (2000) 2:521-30.