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.
Zhang
Xiaohong
X
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Yuan
Zhigang
Z
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Zhang
Yingtao
Y
Department of Pathology and Cell Biology, College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Yong
Sarah
S
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Salas-Burgos
Alexis
A
Departamento de Fisiopatologia, Facultad de Ciencias Biologicas, Universidad de Concepcion, Casilla 160-C Concepcion, Chile.
Koomen
John
J
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Olashaw
Nancy
N
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Parsons
J Thomas
JT
Department of Microbiology, Health Sciences Center, University of Virginia, Charlottesville, VA 22903, USA.
Yang
Xiang-Jiao
XJ
Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montreal, QC H3A 1A1, Canada.
Dent
Sharon R
SR
Department of Biochemistry and Molecular Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Yao
Tso-Pang
TP
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Lane
William S
WS
Microchemistry and Proteomics Analysis Facility, Harvard University, Cambridge, MA 02138, USA.
Seto
Edward
E
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: ed.seto@moffitt.org.
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
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