title: CYK4 inhibits Rac1-dependent PAK1 and ARHGEF7 effector pathways during cytokinesis.
abstract: In mitosis, animal cells lose their adhesion to the surrounding surfaces and become rounded. During mitotic exit, they reestablish these adhesions and at the same time physically contract and divide. How these competing processes are spatially segregated at the cell cortex remains mysterious. To address this question, we define the specific effector pathways used by RhoA and Rac1 in mitotic cells. We demonstrate that the MKlp1-CYK4 centralspindlin complex is a guanosine triphosphatase-activating protein (GAP) for Rac1 and not RhoA and that CYK4 negatively regulated Rac1 activity at the cell equator in anaphase. Cells expressing a CYK4 GAP mutant had defects in cytokinesis and showed elevated staining for the cell adhesion marker vinculin. These defects could be rescued by depletion of ARHGEF7 and p21-activated kinase, Rac1-specific effector proteins required for cell adhesion. Based on these findings, we propose that CYK4 GAP activity is required during anaphase to inhibit Rac1-dependent effector pathways associated with control of cell spreading and adhesion.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, England, UK.
authors.forename: Ricardo Nunes
authors.initials: RN
authors.lastname: Bastos
authors.forename: Xenia
authors.initials: X
authors.lastname: Penate
authors.forename: Michelle
authors.initials: M
authors.lastname: Bates
authors.forename: Dean
authors.initials: D
authors.lastname: Hammond
authors.forename: Francis A
authors.initials: FA
authors.lastname: Barr
mesh_terms: D000705:Anaphase / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D048749:Cytokinesis / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D016596:Vinculin / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C092935:KIF23 protein, human; D008869:Microtubule-Associated Proteins; C107953:RAC1 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; C115995:mgcRacGAP; C066737:RHOA protein, human; D016596:Vinculin; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein