title: TRPM4 Is a Novel Component of the Adhesome Required for Focal Adhesion Disassembly, Migration and Contractility.
abstract: Cellular migration and contractility are fundamental processes that are regulated by a variety of concerted mechanisms such as cytoskeleton rearrangements, focal adhesion turnover, and Ca2+ oscillations. TRPM4 is a Ca2+-activated non-selective cationic channel (Ca2+-NSCC) that conducts monovalent but not divalent cations. Here, we used a mass spectrometry-based proteomics approach to identify putative TRPM4-associated proteins. Interestingly, the largest group of these proteins has actin cytoskeleton-related functions, and among these nine are specifically annotated as focal adhesion-related proteins. Consistent with these results, we found that TRPM4 localizes to focal adhesions in cells from different cellular lineages. We show that suppression of TRPM4 in MEFs impacts turnover of focal adhesions, serum-induced Ca2+ influx, focal adhesion kinase (FAK) and Rac activities, and results in reduced cellular spreading, migration and contractile behavior. Finally, we demonstrate that the inhibition of TRPM4 activity alters cellular contractility in vivo, affecting cutaneous wound healing. Together, these findings provide the first evidence, to our knowledge, for a TRP channel specifically localized to focal adhesions, where it performs a central role in modulating cellular migration and contractility.
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California Davis, Davis, California, United States of America.
authors.forename: Mónica
authors.initials: M
authors.lastname: Cáceres
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Liliana
authors.initials: L
authors.lastname: Ortiz
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile; Programa de Anatomía y Biología del Desarrollo, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Recabarren
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Anibal
authors.initials: A
authors.lastname: Romero
authors.affiliation: Programa de Anatomía y Biología del Desarrollo, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Alicia
authors.initials: A
authors.lastname: Colombo
authors.affiliation: Section on Cellular Signaling, Program in Developmental Biology, National Institute of Child Health and Human Development (NICHD), National Institute of Health, Bethesda, Maryland, United States of America.
authors.forename: Elías
authors.initials: E
authors.lastname: Leiva-Salcedo
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Diego
authors.initials: D
authors.lastname: Varela
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: José
authors.initials: J
authors.lastname: Rivas
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Ian
authors.initials: I
authors.lastname: Silva
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Diego
authors.initials: D
authors.lastname: Morales
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Camilo
authors.initials: C
authors.lastname: Campusano
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Oscar
authors.initials: O
authors.lastname: Almarza
authors.affiliation: Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile; Facultad de Medicina, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Simon
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Hector
authors.initials: H
authors.lastname: Toledo
authors.affiliation: Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California Davis, Davis, California, United States of America; Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Kang-Sik
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California Davis, Davis, California, United States of America; Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Trimmer
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California Davis, Davis, California, United States of America.
authors.forename: Oscar
authors.initials: O
authors.lastname: Cerda
mesh_terms: D000199:Actins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D019070:Cell Lineage; D002465:Cell Movement / Q000235:genetics; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009119:Muscle Contraction / Q000235:genetics*; D010766:Phosphorylation; D040901:Proteomics; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human; D051416:Focal Adhesion Protein-Tyrosine Kinases; D002118:Calcium