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.
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.
Cytoskeleton and Cancer Unit St. Vincent's Institute of Medical Research, University of Melbourne, 3065 Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, 3065 Victoria, Australia.
Alice V
AV
Schofield
Cytoskeleton and Cancer Unit St. Vincent's Institute of Medical Research, University of Melbourne, 3065 Victoria, Australia.
Cristina
C
Gamell
Cell Cycle and Cancer Unit St. Vincent's Institute of Medical Research, University of Melbourne, 3065 Victoria, Australia.
Randy
R
Suryadinata
Department of Medicine, St. Vincent's Hospital, University of Melbourne, 3065 Victoria, Australia; Cell Cycle and Cancer Unit St. Vincent's Institute of Medical Research, University of Melbourne, 3065 Victoria, Australia.
Boris
B
Sarcevic
Cytoskeleton and Cancer Unit St. Vincent's Institute of Medical Research, University of Melbourne, 3065 Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, 3065 Victoria, Australia. Electronic address: obernard@svi.edu.au.
Ora
O
Bernard
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010616:Phenanthrenes; D010766:Phosphorylation; D011419:Propidium / Q000494:pharmacology; D011485:Protein Binding; D016196:S Phase; D054460:rho-Associated Kinases / Q000378:metabolism*
C116344:9-triphenylphosphoniomethylphenanthrene chloride; D009419:Nerve Tissue Proteins; D010616:Phenanthrenes; C118136:TPPP protein, human; D011419:Propidium; D054460:rho-Associated Kinases; D016203:CDC2 Protein Kinase