title: A lateral signalling pathway coordinates shape volatility during cell migration.
abstract: Cell migration is fundamental for both physiological and pathological processes. Migrating cells usually display high dynamics in morphology, which is orchestrated by an integrative array of signalling pathways. Here we identify a novel pathway, we term lateral signalling, comprised of the planar cell polarity (PCP) protein Pk1 and the RhoGAPs, Arhgap21/23. We show that the Pk1-Arhgap21/23 complex inhibits RhoA, is localized on the non-protrusive lateral membrane cortex and its disruption leads to the disorganization of the actomyosin network and altered focal adhesion dynamics. Pk1-mediated lateral signalling confines protrusive activity and is regulated by Smurf2, an E3 ubiquitin ligase in the PCP pathway. Furthermore, we demonstrate that dynamic interplay between lateral and protrusive signalling generates cyclical fluctuations in cell shape that we quantify here as shape volatility, which strongly correlates with migration speed. These studies uncover a previously unrecognized lateral signalling pathway that coordinates shape volatility during productive cell migration.
authors.affiliation: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Valbona
authors.initials: V
authors.lastname: Luga
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Armitage
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5.
authors.forename: Martin
authors.initials: M
authors.lastname: Musiol
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, The Terrence Donnelly Centre for Cellular and Biomolecular Research, Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Amy
authors.initials: A
authors.lastname: Won
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, The Terrence Donnelly Centre for Cellular and Biomolecular Research, Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Yip
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Plotnikov
authors.affiliation: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology*; D048430:Cell Shape / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D059008:Time-Lapse Imaging / Q000379:methods; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C459590:ARHGAP21 protein, human; C495458:ARHGAP23 protein, human; D020690:GTPase-Activating Proteins; C066737:RHOA protein, human; D000205:Actomyosin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D020742:rhoA GTP-Binding Protein