title: HDAC6 modulates cell motility by altering the acetylation level of cortactin.
abstract: Histone deacetylase 6 (HDAC6) is a tubulin-specific deacetylase that regulates microtubule-dependent cell movement. In this study, we identify the F-actin-binding protein cortactin as a HDAC6 substrate. We demonstrate that HDAC6 binds cortactin and that overexpression of HDAC6 leads to hypoacetylation of cortactin, whereas inhibition of HDAC6 activity leads to cortactin hyperacetylation. HDAC6 alters the ability of cortactin to bind F-actin by modulating a "charge patch" in its repeat region. Introduction of charge-preserving or charge-neutralizing mutations in this cortactin repeat region correlates with the gain or loss of F-actin binding ability, respectively. Cells expressing a charge-neutralizing cortactin mutant were less motile than control cells or cells expressing a charge-preserving mutant. These findings suggest that, in addition to its role in microtubule-dependent cell motility, HDAC6 influences actin-dependent cell motility by altering the acetylation status of cortactin, which, in turn, changes the F-actin binding activity of cortactin.
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Pathology and Cell Biology, College of Medicine, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Yong
authors.affiliation: Departamento de Fisiopatologia, Facultad de Ciencias Biologicas, Universidad de Concepcion, Casilla 160-C Concepcion, Chile.
authors.forename: Alexis
authors.initials: A
authors.lastname: Salas-Burgos
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koomen
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Olashaw
authors.affiliation: Department of Microbiology, Health Sciences Center, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Parsons
authors.affiliation: Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montreal, QC H3A 1A1, Canada.
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Dent
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.affiliation: Microchemistry and Proteomics Analysis Facility, Harvard University, Cambridge, MA 02138, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Lane
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: ed.seto@moffitt.org.
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
mesh_terms: D000107:Acetylation; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D051356:Cortactin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; D051356:Cortactin; D051548:Histone Acetyltransferases; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D011994:Recombinant Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C495868:CTTN protein, human; C495869:Cttn protein, mouse; C433811:HDAC6 protein, human