Defects in chromosome segregation can generate aneuploidy, a condition that is found in almost all human tumors and is the major cause of miscarriages and birth defects. The complex process of chromosome segregation must be highly regulated to ensure fidelity and prevent aneuploidy. Many of the mitotic events are regulated by the kinetochore, a proteinacous structure assembled on centromeric DNA that coordinates at least three mitotic functions. First, the kinetochore is the chromosomal site of microtubule attachment and movement. Second, the kinetochore is the major site of cohesion between sister chromatids. This cohesion must be maintained through metaphase and its dissolution is the critical event that triggers anaphase. Third, kinetochores that are not attached to microtubules send signals to the cell cycle machinery to prevent this dissolution of cohesion, a process referred to as the spindle assembly checkpoint. This checkpoint ensures that all chromatids are attached before the onset of anaphase. How the kinetochore coordinates these various functions is a critical unanswered question.

The Stukenberg lab studies kinetochores using egg extracts, cells and embryos of the frog Xenopus laevis. The extracts of Xenopus eggs are the only system that can assemble functional kinetochores in vitro, allowing us to biochemically dissect kinetochore assembly, structure and function. Moreover, we utilize two in vivo systems, Xenopus tissue culture cells and Xenopus embryos, to test predictions from our in vitro results.

Current work has focused on the Aurora B kinase which is a critical mitotic regulator that localizes to the inner centromere region from prophase to anaphase. We recently discovered that Aurora B regulates microtubule dynamics, chromosome congression and the spindle checkpoint. We are dissecting how Aurora B itself is regulated and identifying the important substrates that are regulated by Aurora B for proper mitotic progression.

The lab is also studying a relatively new component of the outer kinetochore that is highly conserved from yeast to humans referred to as the Ndc80 complex. The Ndc80 complex is required for proper kinetochore assembly, microtubule binding and chromosome congression. In collaboration with our neighbors, the Burke lab, we have shown that the complex is a critical mediator of the spindle checkpoint. An exciting question for the future is how the Ndc80 complex and Aurora B can coordinate microtubule binding and spindle checkpoint signaling.

Selected References

Fuller BG, Lampson MA, Foley EA, Rosasco-Nitcher S, Le KV, Tobelmann P,Brautigan DL, Stukenberg PT, Kapoor TM. (2008) "Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient." Nature. Jun 453(7198):1132-6. Epub 2008 May 7. [PubMed]

Emanuele MJ, Lan W, Jwa M, Miller SA, Chan CS, Stukenberg PT. (2008) "Aurora B kinase and protein phosphatase 1 have opposing roles in modulating kinetochore assembly." J Cell Biol. Apr 181:241-54. [PubMed]

Burke DJ, Stukenberg PT. (2008) "Linking kinetochore-microtubule binding to the spindle checkpoint." Dev Cell. 14:474-9. [PubMed]

Rosasco-Nitcher SE, Lan W, Khorasanizadeh S, Stukenberg PT. (2008) "Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation." Science. Jan 319(5862):469-72. [PubMed]

Emanuele MJ, Stukenberg PT. (2007) "Xenopus Cep57 is a novel kinetochore component involved in microtubule attachment." Cell. Sep 130:893-905. [PubMed]

Knowlton AL, Lan W, Stukenberg PT. (2006) "Aurora B is enriched at merotelic attachment sites, where it regulates MCAK." Curr Biol. Sep 16(17):1705-10. [PubMed]