Activated I-BAR IRSp53 clustering controls the formation of VASP-actin–based membrane protrusions

Funding Information: Acknowledgments: The computations were supported by the University of Chicago Research Funding Information: The computations were supported by the University of Chicago Research Computing Center (RCC). We thank E. Coudrier and C. Simon for insightful discussions. We also thank F. Di Federico for handling plasmids, F. Tabarin-Cayrac for cell sorting, and A.-S. Mace for ImageJ programming assistance. F.-C.T., C.L.C., and P.B. are members of the CNRS consortium AQV. F.-C.T. and P.B. are members of the Labex Cell(n)Scale (ANR-11-LABX0038) and Paris Sciences et Lettres (ANR-10-IDEX-0001-02). We acknowledge the Cell and Tissue Imaging Core facility (PICT IBiSA), Institut Curie, member of the French National Research Infrastructure France-BioImaging (ANR10-INBS-04). This work was supported by Human Frontier Science Program (HFSP) grant RGP0005/2016 (to F.-C.T., J.M.H., G.A.V., P.L., and P.B.), Institut Curie and the Centre National de la Recherche Scientifique (CNRS) (to F.-C.T., J.M.H., and P.B.), Marie Curie actions H2020-MSCA-IF-2014 (to F.-C.T.), EMBO Long-Term fellowship ALTF 1527-2014 (to F.-C.T.), Pasteur Foundation Fellowship (to J.M.H.), Agence Nationale pour la Recherche ANR-20-CE13-0032 (to J.M.H. and P.B.) and ANR-20-CE11-0010-01 (to F.-C.T), Université Paris Sciences et Lettres-QLife Institute ANR-17-CONV-0005 Q-LIFE (to P.B.), FY 2015 Researcher Exchange Program between the Japan Society for the Promotion of Science and Academy of Finland (to Y.S.), the Takeda Science Foundation (to Y.S.), the Wesco Scientific Promotion Foundation (to Y.S.), Agence Nationale pour la Recherche ANR-18-CE13-0026-01 and ANR-21-CE13-0010-03 (to C.L.C.), Cancer Society Finland 4705949 (to P.L.), and U.S. National Institutes of Health (NIH) Institute of General Medical Sciences (NIGMS) grant R01-GM063796 (to G.A.V. and Z.J.) Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.Filopodia are actin-rich membrane protrusions essential for cell morphogenesis, motility, and cancer invasion. How cells control filopodium initiation on the plasma membrane remains elusive. We performed experiments in cellulo, in vitro, and in silico to unravel the mechanism of filopodium initiation driven by the membrane curvature sensor IRSp53 (insulin receptor substrate protein of 53 kDa). We showed that full-length IRSp53 self-assembles into clusters on membranes depending on PIP2. Using well-controlled in vitro reconstitution systems, we demonstrated that IRSp53 clusters recruit the actin polymerase VASP (vasodilator-stimulated phosphoprotein) to assemble actin filaments locally on membranes, leading to the generation of actin-filled membrane protrusions reminiscent of filopodia. By pulling membrane nanotubes from live cells, we observed that IRSp53 can only be enriched and trigger actin assembly in nanotubes at highly dynamic membrane regions. Our work supports a regulation mechanism of IRSp53 in its attributes of curvature sensation and partner recruitment to ensure a precise spatial-temporal control of filopodium initiation.Peer reviewe

Liability in Software Engineering: Overview of the LISE Approach and Illustration on a Case Study

© ACM – 2010. This is the authors' pre-version of the work. It is posted here by permission of ACM for your personal use. Not for redistribution. The definitive version was published in the Proceedings of the 32nd ACM/IEEE international Conference on Software Engineering (ICSE'10) - Volume 1 – 978-1-60558-719-6/10/05 – (May 2-8 – 2010) http://doi.acm.org/10.1145/1806799.1806823LISE is a multidisciplinary project involving lawyers and computer scientists with the aim to put forward a set of methods and tools to (1) define software liability in a precise and unambiguous way and (2) establish such liability in case of incident. This report provides an overview of the overall approach taken in the project based on a case study. The case study illustrates a situation where, in order to reduce legal uncertainties, the parties to a contract wish to include in the agreement specific clauses to define as precisely as possible the share of liabilities between them for the main types of failures of the system

TOR kinase complexes and cell migration

Cell migration is a fundamental process in a wide array of biological and pathological responses. It is regulated by complex signal transduction pathways in response to external cues that couple to growth factor and chemokine receptors. In recent years, the target of rapamycin (TOR) kinase, as part of either TOR complex 1 (TORC1) or TOR complex 2 (TORC2), has been shown to be an important signaling component linking external signals to the cytoskeletal machinery in a variety of cell types and organisms. Thus, these complexes have emerged as key regulators of cell migration and chemotaxis

Consentement et traitement de données à caractère personnel.

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Chronique du droit de l'internet.

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Integrin Facilitates the Internalization of TAT Peptide Conjugated to RGD Motif in Model Lipid Membranes

Abstract In recent years, targeted drug delivery has attracted a great interest for enhanced therapeutic efficiency, with diminished side effects, especially in cancer therapy. Cell penetrating peptides (CPPs) like HIV1−TAT peptides, appear to be the perfect vectors for translocating drugs or other cargoes across the plasma membrane, but their application is limited mostly due to insufficient specificity for intended targets. Although these molecules were successfully used, the mechanism by which the peptides enter the cell interior still needs to be clarified. The tripeptide motif RGD (arginine−glycine−aspartate), found in extracellular matrix proteins has high affinity for integrin receptors overexpressed in cancer and it is involved in different phases of disease progression, including proliferation, invasion and migration. Discovery of new peptides with high binding affinity for disease receptors and permeability of plasma membranes is desirable for both, development of targeted drug delivery systems and early detection and diagnosis. To complement the TAT peptide with specific targeting ability, we conjugated it with an integrin‐binding RGD motif. Although the idea of RGD−CPPs conjugates is not entirely new, [1] here we describe the permeability abilities and specificity of integrin receptors of RGD−TAT peptides in model membranes. Our findings reveal that this novel RGD sequence based on TAT peptide maintains its ability to permeate lipid membranes and exhibits specificity for integrin receptors embedded in giant unilamellar vesicles. This promising outcome suggests that the RGD−TAT peptide has significant potential for applications in the field of targeted drug delivery systems

Oxorhenium-Mediated Assembly of Noncyclic Selective Integrin Antagonists: A Combinatorial Approach

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