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Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling

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Science  12 Jun 2015:
Vol. 348, Issue 6240, pp. 1264-1267
DOI: 10.1126/science.aaa4055

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How cells sense connected chromosomes

Cells have a “checkpoint” that pauses cell division until all chromosomes are properly arranged on the mitotic spindle to allow precise distribution of one copy of each chromosome to each daughter cell. Hiruma et al. and Ji et al. explain the molecular mechanism by which cells sense that they are ready to divide. The protein kinase MPS1 associates with a protein complex at the kinetochore of the chromosome. Its activity produces signals that pause the cell cycle. When the chromosome becomes properly attached to the mitotic spindle, microtubules of the spindle physically compete for binding to the same site on the kinetochore where MPS1 is bound. Thus, once the kinetochore is properly attached, MPS1 dissociates, the inhibitory signal is lost, and cell division is allowed to proceed.

Science, this issue pp. 1264 and 1260

Abstract

Cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules through kinetochores and the spindle assembly checkpoint (SAC) is satisfied. We show that the amino-terminal localization module of the SAC protein kinase MPS1 (monopolar spindle 1) directly interacts with the HEC1 (highly expressed in cancer 1) calponin homology domain in the NDC80 (nuclear division cycle 80) kinetochore complex in vitro, in a phosphorylation-dependent manner. Microtubule polymers disrupted this interaction. In cells, MPS1 binding to kinetochores or to ectopic NDC80 complexes was prevented by end-on microtubule attachment, independent of known kinetochore protein-removal mechanisms. Competition for kinetochore binding between SAC proteins and microtubules provides a direct and perhaps evolutionarily conserved way to detect a properly organized spindle ready for cell division.

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