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HDAC6 modulates cell motility by altering the acetylation level of cortactin.

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.

Pubmed ID: 17643370

Authors

  • Zhang X
  • Yuan Z
  • Zhang Y
  • Yong S
  • Salas-Burgos A
  • Koomen J
  • Olashaw N
  • Parsons JT
  • Yang XJ
  • Dent SR
  • Yao TP
  • Lane WS
  • Seto E

Journal

Molecular cell

Publication Data

July 20, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA109699
  • Agency: NIGMS NIH HHS, Id: GM58486
  • Agency: NCI NIH HHS, Id: R01 CA109699
  • Agency: NCI NIH HHS, Id: R01 CA109699-01
  • Agency: NCI NIH HHS, Id: R01 CA109699-02
  • Agency: NCI NIH HHS, Id: R01 CA109699-03
  • Agency: NCI NIH HHS, Id: R01 CA109699-04
  • Agency: NCI NIH HHS, Id: R01 CA109699-05
  • Agency: NIGMS NIH HHS, Id: R01 GM058486
  • Agency: NIGMS NIH HHS, Id: R01 GM058486-05
  • Agency: NIGMS NIH HHS, Id: R01 GM058486-06
  • Agency: NIGMS NIH HHS, Id: R01 GM058486-07
  • Agency: NIGMS NIH HHS, Id: R01 GM058486-08
  • Agency: NINDS NIH HHS, Id: R01 NS054022
  • Agency: NINDS NIH HHS, Id: R01 NS054022-02

Mesh Terms

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