Abstract
The two members of the Rho-associated coiled-coil kinase (ROCK1 and 2) family are established regulators of actin dynamics that are involved in the regulation of the cell cycle as well as cell motility and invasion. Here, we discovered a novel signaling pathway whereby ROCK regulates microtubule (MT) acetylation via phosphorylation of the tubulin polymerization promoting protein 1 (TPPP1/p25). We show that ROCK phosphorylation of TPPP1 inhibits the interaction between TPPP1 and histone deacetylase 6 (HDAC6), which in turn results in increased HDAC6 activity followed by a decrease in MT acetylation. As a consequence, we show that TPPP1 phosphorylation by ROCK increases cell migration and invasion via modulation of cellular acetyl MT levels. We establish here that the ROCK-TPPP1-HDAC6 signaling pathway is important for the regulation of cell migration and invasion.
Highlights
We show that Rho-associated coiled-coil kinase (ROCK) phosphorylation of TPPP1 inhibits the interaction between TPPP1 and histone deacetylase 6 (HDAC6), which in turn results in increased HDAC6 activity followed by a decrease in MT acetylation
We showed that inhibition of LIM kinases (LIMK) activity decreased the phosphorylation of its substrate cofilin (Fig. 2B), the level of TPPP1 phosphorylation by ROCK was unchanged (A, lane 5), confirming that TPPP1 is phosphorylated by ROCK in vitro
We demonstrated that inhibition of ROCK activity, demonstrated by decreased pMLC levels in cell lysates, significantly decreased TPPP1 phosphorylation compared with the controls in HEK293T (Fig. 2C Lanes 1 and 2) as well as in U2OS cells (Fig. 2D)
Summary
Conclusion: ROCK phosphorylation of TPPP1 is a novel signaling pathway that regulates cell migration via increased HDAC6 activity and reduced MT acetylation. Significance: This newly discovered ROCK/TPPP/HDAC6/MT signaling pathway might have important implications for cell motility and invasion. We discovered a novel signaling pathway whereby ROCK regulates microtubule (MT) acetylation via phosphorylation of the tubulin polymerization promoting protein 1 (TPPP1/p25). We show that ROCK phosphorylation of TPPP1 inhibits the interaction between TPPP1 and histone deacetylase 6 (HDAC6), which in turn results in increased HDAC6 activity followed by a decrease in MT acetylation. We report here that ROCK-mediated phosphorylation of TPPP1 inhibits the TPPP1/HDAC6 interaction to drive a decrease in acetylated MT levels in cells, resulting in increased cell migration and invasion
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
