HDAC6 modulates cell motility by altering the acetylation level of cortactin

Xiaohong Zhang; Zhigang Yuan; Yingtao Zhang; Sarah Yong; Alexis Salas-Burgos; John Koomen; Nancy Olashaw; J Thomas Parsons; Xiang-Jiao Yang; Sharon R Dent; Tso-Pang Yao; William S Lane; Edward Seto

doi:10.1016/j.molcel.2007.05.033

HDAC6 modulates cell motility by altering the acetylation level of cortactin

Mol Cell. 2007 Jul 20;27(2):197-213. doi: 10.1016/j.molcel.2007.05.033.

Authors

Affiliations

¹ Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
² Department of Pathology and Cell Biology, College of Medicine, University of South Florida, Tampa, FL 33612, USA.
³ Departamento de Fisiopatologia, Facultad de Ciencias Biologicas, Universidad de Concepcion, Casilla 160-C Concepcion, Chile.
⁴ Department of Microbiology, Health Sciences Center, University of Virginia, Charlottesville, VA 22903, USA.
⁵ Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montreal, QC H3A 1A1, Canada.
⁶ Department of Biochemistry and Molecular Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
⁸ Microchemistry and Proteomics Analysis Facility, Harvard University, Cambridge, MA 02138, USA.
⁹ Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: ed.seto@moffitt.org.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Actins / metabolism
Amino Acid Sequence
Amino Acid Substitution
Animals
Cell Cycle Proteins / metabolism
Cell Movement / physiology*
Cortactin / chemistry
Cortactin / genetics
Cortactin / metabolism*
HeLa Cells
Histone Acetyltransferases / metabolism
Histone Deacetylase 6
Histone Deacetylase Inhibitors
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Humans
In Vitro Techniques
Mice
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
NIH 3T3 Cells
Protein Binding
Rabbits
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Repetitive Sequences, Amino Acid
Sequence Homology, Amino Acid
Transcription Factors / metabolism
p300-CBP Transcription Factors

Substances

Actins
CTTN protein, human
Cell Cycle Proteins
Cortactin
Cttn protein, mouse
Histone Deacetylase Inhibitors
Recombinant Proteins
Transcription Factors
Histone Acetyltransferases
p300-CBP Transcription Factors
p300-CBP-associated factor
HDAC6 protein, human
Histone Deacetylase 6
Histone Deacetylases

Associated data

PDB/2F9X

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding