title: The END network couples spindle pole assembly to inhibition of the anaphase-promoting complex/cyclosome in early mitosis.
abstract: Cyclin-dependent kinase 1 (Cdk1) initiates mitosis and later activates the anaphase-promoting complex/cyclosome (APC/C) to destroy cyclins. Kinetochore-derived checkpoint signaling delays APC/C-dependent cyclin B destruction, and checkpoint-independent mechanisms cooperate to limit APC/C activity when kinetochores lack checkpoint components in early mitosis. The APC/C and cyclin B localize to the spindle and poles, but the significance and regulation of these populations remain unclear. Here we describe a critical spindle pole-associated mechanism, called the END (Emi1/NuMA/dynein-dynactin) network, that spatially restricts APC/C activity in early mitosis. The APC/C inhibitor Emi1 binds the spindle-organizing NuMA/dynein-dynactin complex to anchor and inhibit the APC/C at spindle poles, and thereby limits destruction of spindle-associated cyclin B. Cyclin B/Cdk1 activity recruits the END network and establishes a positive feedback loop to stabilize spindle-associated cyclin B critical for spindle assembly. The organization of the APC/C on the spindle also provides a framework for understanding microtubule-dependent organization of protein destruction.
authors.affiliation: Program in Cancer Biology, Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Ban
authors.forename: Jorge Z
authors.initials: JZ
authors.lastname: Torres
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Miller
authors.forename: Alexei
authors.initials: A
authors.lastname: Mikhailov
authors.forename: Maxence V
authors.initials: MV
authors.lastname: Nachury
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Tung
authors.forename: Conly L
authors.initials: CL
authors.lastname: Rieder
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
mesh_terms: D000705:Anaphase / Q000502:physiology*; D064173:Anaphase-Promoting Complex-Cyclosome; D034961:Antigens, Nuclear / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002877:Chromosomes, Human / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D008941:Spindle Apparatus / Q000201:enzymology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D019926:Cyclin B; D000072159:Dynactin Complex; D044783:F-Box Proteins; C498960:FBXO5 protein, human; D008869:Microtubule-Associated Proteins; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D016203:CDC2 Protein Kinase; D004398:Dyneins