Tubulin Polymerization Promoting Protein 1 (Tppp1) Phosphorylation by Rho-associated Coiled-coil Kinase (Rock) and Cyclin-dependent Kinase 1 (Cdk1) Inhibits Microtubule Dynamics to Increase Cell Proliferation |
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| Authors: | Alice V Schofield Cristina Gamell Randy Suryadinata Boris Sarcevic Ora Bernard |
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| Institution: | From the ‡Cytoskeleton and Cancer Unit and ;the ¶Cell Cycle and Cancer Unit St. Vincent''s Institute of Medical Research, and ;the §Department of Medicine, St. Vincent''s Hospital, University of Melbourne, 3065 Victoria, Australia |
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| Abstract: | Tubulin polymerization promoting protein 1 (Tppp1) regulates microtubule (MT) dynamics via promoting MT polymerization and inhibiting histone deacetylase 6 (Hdac6) activity to increase MT acetylation. Our results reveal that as a consequence, Tppp1 inhibits cell proliferation by delaying the G1/S-phase and the mitosis to G1-phase transitions. We show that phosphorylation of Tppp1 by Rho-associated coiled-coil kinase (Rock) prevents its Hdac6 inhibitory activity to enable cells to enter S-phase. Whereas, our analysis of the role of Tppp1 during mitosis revealed that inhibition of its MT polymerizing and Hdac6 regulatory activities were necessary for cells to re-enter the G1-phase. During this investigation, we also discovered that Tppp1 is a novel Cyclin B/Cdk1 (cyclin-dependent kinase) substrate and that Cdk phosphorylation of Tppp1 inhibits its MT polymerizing activity. Overall, our results show that dual Rock and Cdk phosphorylation of Tppp1 inhibits its regulation of the cell cycle to increase cell proliferation. |
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| Keywords: | Cell Cycle Cell Proliferation Microtubules Phosphorylation Signal Transduction Cyclin-dependent Kinase Rho Kinase TPPP1/p25 |
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