title: Kindlin1 regulates microtubule function to ensure normal mitosis.
abstract: Loss of Kindlin 1 (Kin1) results in the skin blistering disorder Kindler Syndrome (KS), whose symptoms also include skin atrophy and reduced keratinocyte proliferation. Kin1 binds to integrins to modulate their activation and more recently it has been shown to regulate mitotic spindles and cell survival in a Plk1-dependent manner. Here we report that short-term Kin1 deletion in mouse skin results in impaired mitosis, which is associated with reduced acetylated tubulin (ac-tub) levels and cell proliferation. In cells, impaired mitosis and reduced ac-tub levels are also accompanied by reduced microtubule stability, all of which are rescued by HDAC6 inhibition. The ability of Kin1 to regulate HDAC6-dependent cellular ac-tub levels is dependent on its phosphorylation by Plk1. Taken together, these data define a novel role for Kin1 in microtubule acetylation and stability and offer a mechanistic insight into how certain KS phenotypes, such as skin atrophy and reduced cell proliferation, arise.
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK v.brunton@ed.ac.uk h.patel@ed.ac.uk.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Patel
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Ifigeneia
authors.initials: I
authors.lastname: Stavrou
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Roshan L
authors.initials: RL
authors.lastname: Shrestha
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK Present address: School of Biological and Chemical Sciences, Queen Mary University of London, London, E11 4NS, UK.
authors.forename: Viji
authors.initials: V
authors.lastname: Draviam
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK v.brunton@ed.ac.uk h.patel@ed.ac.uk.
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
mesh_terms: D000107:Acetylation; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism; D017353:Gene Deletion; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D014404:Tubulin; D000097869:Polo-Like Kinase 1; C475301:FERMT1 protein, human; C534220:kindlin-1 protein, mouse; C499033:Hdac6 protein, mouse
keywords: HDAC6; Kindlin1; Plk1; microtubules; mitosis