title: Tubulin polymerization promoting protein 1 (TPPP1) increases β-catenin expression through inhibition of HDAC6 activity in U2OS osteosarcoma cells.
abstract: The Rho-associated coiled-coil kinase (ROCK) family of proteins, including ROCK1 and ROCK2, are key regulators of actin and intermediate filament morphology. The newly discovered ROCK substrate Tubulin polymerization promoting protein 1 (TPPP1) promotes microtubule polymerization and inhibits the activity of Histone deacetylase 6 (HDAC6). The effect of TPPP1 on HDAC6 activity is inhibited by ROCK signaling. Moreover, it was recently demonstrated that ROCK activity increases the cellular expression of the oncogene β-catenin, which is a HDAC6 substrate. In this study, we investigated the interplay between ROCK-TPPP1-HDAC6 signaling and β-catenin expression. We demonstrate that β-catenin expression is increased with ROCK signaling activation and is reduced with increased TPPP1 expression in U2OS cells. Further investigation revealed that ROCK-mediated TPPP1 phosphorylation, which prevents its binding to HDAC6, negates TPPP1-mediated reduction in β-catenin expression. We also show that increased HDAC6 activity resulting from ROCK signaling activation reduced β-catenin acetylation at Lys-49, which was also accompanied by its decreased phosphorylation by Caesin kinase 1 (CK1) and Glycogen synthase kinase 3β (GSK3β), thus preventing its proteasomal degradation. Overall, our results suggest that ROCK regulates β-catenin stability in cells via preventing TPPP1-mediated inhibition of HDAC6 activity, to reduce its acetylation and degradation via phosphorylation by CK1 and GSK3β.
authors.affiliation: Cytoskeleton and Cancer Unit, St. Vincent's Institute of Medical Research, Australia.
authors.forename: Alice V
authors.initials: AV
authors.lastname: Schofield
authors.forename: Cristina
authors.initials: C
authors.lastname: Gamell
authors.forename: Ora
authors.initials: O
authors.lastname: Bernard
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D012516:Osteosarcoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D051176:beta Catenin; D054460:rho-Associated Kinases; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: CK1; Deacetylation; GSK3β; HDAC6; Microtubule; Mitogen; Phosphorylation; ROCK; ROCK1; TPPP1; caesin kinase 1; glycogen synthase kinase 3β; histone deacetylase 6; rho-associated coiled-coil kinase; tubulin polymerization promoting protein 1; β-Catenin; β-TrCP; β-transducin repeat-containing protein