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The END network couples spindle pole assembly to inhibition of the anaphase-promoting complex/cyclosome in early mitosis.

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.

Pubmed ID: 17609108

Authors

  • Ban KH
  • Torres JZ
  • Miller JJ
  • Mikhailov A
  • Nachury MV
  • Tung JJ
  • Rieder CL
  • Jackson PK

Journal

Developmental cell

Publication Data

July 4, 2007

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM07365
  • Agency: PHS HHS, Id: GMS 40198
  • Agency: NIGMS NIH HHS, Id: R01 GM54811
  • Agency: NIGMS NIH HHS, Id: R01 GM60439
  • Agency: NIGMS NIH HHS, Id: R37 GM040198
  • Agency: NCI NIH HHS, Id: T32 CA09302-27

Mesh Terms

  • Anaphase
  • Anaphase-Promoting Complex-Cyclosome
  • Antigens, Nuclear
  • CDC2 Protein Kinase
  • Cell Cycle Proteins
  • Chromosomes, Human
  • Cyclin B
  • Dyneins
  • F-Box Proteins
  • Feedback, Physiological
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Microtubule-Associated Proteins
  • Nuclear Matrix-Associated Proteins
  • Protein Binding
  • Spindle Apparatus
  • Ubiquitin-Protein Ligase Complexes