P. Todd Stukenberg
- BA, Colgate University
- Postdoc, Harvard Medical School
- PhD, Sloan-Kettering Cancer Institute, and Cornell Medical School, NY, NY.
- Professor, Biochemistry and Molecular Genetics
Mechanisms of chromosome segregation in Mitosis and generation of Chromosomal Instability in tumors
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. In fact, in a large percentage of tumors the fidelity of mitosis is decreased which can drive tumor progression.
Many of the events of mitosis are regulated by the kinetochores and the inner centromere. Kinetochore are assembled on centromeric DNA that bind microtubules and move chromosomes on the mitotic spindle. They also generate the spindle checkpoint signal the ensures that all of the kinetochores are bound to microtubules before they undergo anaphase segregation of chromatids. Inner centromeres are the chromosome region between kinetochores. They are the major site of cohesion between sister chromatids and also contain regulators of kinetochores. This cohesion must be maintained through metaphase and its dissolution is the critical event that triggers anaphase.
How kinetochores and inner centromeres coordinate the events of mitosis underlie a number of critical unanswered questions with direct relevance to cancer biology. The Stukenberg lab studies the pathways that 1) power the movements of chromosome movement using the energy stored in the microtubule polymer 2) ensure that the microtubules bound to kinetochores emanate from the correct poles to properly segregate the two sister chromatids in anaphase 3) connect the attachments of microtubules to kinetochores with the generation of the spindle checkpoint signal 4) regulate the transcription from inner centromeres on mitotic chromosomes 5) lower the fidelity of segregation in tumors.
Much of our 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. Aurora kinases have become important drug targets for chemotherapeutics. We discovered that Aurora B regulates microtubule dynamics, microtubule attachments to kinetochores and the spindle checkpoint. We are dissecting how Aurora B is regulated and identifying the important substrates that are regulated by Aurora B for proper mitotic progression.
The lab performed some of the initial characterization and identified the subunits of the Ndc80 complex, which is the key microtubule attachment point of kinetochores to microtubules. We demonstrated that the Ndc80 complex is required for proper kinetochore assembly, movements of chromosomes and generating the spindle checkpoint signals. We are studying the biophysics and cell biology of Ndc80 to understand how kinetochores move chromosomes and how the spindle checkpoint is coupled to microtubule attachments.
We also study how tumors missegregate chromosomes at a higher rate than non-transformed cells, which is known as “Chromosomal Instability”. We utilize bioinformatic approaches to dissect the changes in human tumors that cause the events and recapitulate those changes in model systems.
- Sivakumar S, Janczyk P, Qu Q, Brautigam C, Stukenberg P, Yu H, Gorbsky G. The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores. eLife. 2016;5. PMID: 26981768 | PMCID: PMC4821802
- Eagleson G, Pfister K, Knowlton A, Skoglund P, Keller R, Stukenberg P. Kif2a depletion generates chromosome segregation and pole coalescence defects in animal caps and inhibits gastrulation of the Xenopus embryo. Molecular biology of the cell. 2015;26(5): 924-37. PMID: 25568341 | PMCID: PMC4342028
- Stukenberg P, Burke D. Connecting the microtubule attachment status of each kinetochore to cell cycle arrest through the spindle assembly checkpoint. Chromosoma. 2015;124(4): 463-80. PMID: 25917595
- Trivedi P, Stukenberg P. A Centromere-Signaling Network Underlies the Coordination among Mitotic Events. Trends in biochemical sciences. 2015;41(2): 160-74. PMID: 26705896 | PMCID: PMC4733523
- Banerjee B, Kestner C, Stukenberg P. EB1 enables spindle microtubules to regulate centromeric recruitment of Aurora B. The Journal of cell biology. 2014;204(6): 947-63. PMID: 24616220 | PMCID: PMC3998792
- Manukyan A, Ludwig K, Sanchez-Manchinelly S, Parsons S, Stukenberg P. A complex of p190RhoGAP-A and anillin modulates RhoA-GTP and the cytokinetic furrow in human cells. Journal of cell science. 2014;128(1): 50-60. PMID: 25359885 | PMCID: PMC4282047
- Matson D, Stukenberg P. CENP-I and Aurora B act as a molecular switch that ties RZZ/Mad1 recruitment to kinetochore attachment status. The Journal of cell biology. 2014;205(4): 541-554. PMID: 24862574 | PMCID: PMC4033774
- Zyłkiewicz E, Stukenberg P. Xenopus egg extracts as a simplified model system for structure-function studies of Dynein regulators. Methods in molecular biology (Clifton, N.J.). 2014;1136 117-33. PMID: 24633797
- Foltz D, Stukenberg P. A new histone at the centromere? Cell. 2012;148(3): 394-6. PMID: 22304909 | PMCID: PMC3404608
- Matson D, Demirel P, Stukenberg P, Burke D. A conserved role for COMA/CENP-H/I/N kinetochore proteins in the spindle checkpoint. Genes & development. 2012;26(6): 542-7. PMID: 22426531 | PMCID: PMC3315115
- Matson D, Stukenberg P. Cdt1 throws kinetochore-microtubule attachments for a loop. Nature cell biology. 2012;14(6): 561-3. PMID: 22643874 | PMCID: PMC3600811
- Niedzialkowska E, Wang F, Porebski P, Minor W, Higgins J, Stukenberg P. Molecular basis for phosphospecific recognition of histone H3 tails by Survivin paralogues at inner centromeres. Molecular biology of the cell. 2012;23(8): 1457-66. PMID: 22357620 | PMCID: PMC3327328
- Utepbergenov D, Derewenda U, Olekhnovich N, Szukalska G, Banerjee B, Hilinski M, Lannigan D, Stukenberg P, Derewenda Z. Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor. Biochemistry. 2012;51(33): 6499-510. PMID: 22846040 | PMCID: PMC3462495
- Matson D, Stukenberg P. Spindle poisons and cell fate: a tale of two pathways. Molecular interventions. 2011;11(2): 141-50. PMID: 21540474 | PMCID: PMC3086919
- Tooley J, Miller S, Stukenberg P. The Ndc80 complex uses a tripartite attachment point to couple microtubule depolymerization to chromosome movement. Molecular biology of the cell. 2011;22(8): 1217-26. PMID: 21325630 | PMCID: PMC3078066
- Tooley J, Stukenberg P. The Ndc80 complex: integrating the kinetochore's many movements. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology. 2011;19(3): 377-91. PMID: 21311965 | PMCID: PMC3148027
- Zheng M, Cierpicki T, Burdette A, Utepbergenov D, Janczyk P, Derewenda U, Stukenberg P, Caldwell K, Derewenda Z. Structural features and chaperone activity of the NudC protein family. Journal of molecular biology. 2011;409(5): 722-41. PMID: 21530541 | PMCID: PMC3159028
- Zyłkiewicz E, Kijańska M, Choi W, Derewenda U, Derewenda Z, Stukenberg P. The N-terminal coiled-coil of Ndel1 is a regulated scaffold that recruits LIS1 to dynein. The Journal of cell biology. 2011;192(3): 433-45. PMID: 21282465 | PMCID: PMC3101096
- Stukenberg P, Foltz D. Kinetochores: orchestrating the chromosomal minuet. Current biology : CB. 2010;20(12): R522-5. PMID: 20620907 | PMCID: PMC3148016
- Wang F, Dai J, Daum J, Niedzialkowska E, Banerjee B, Stukenberg P, Gorbsky G, Higgins J. Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science (New York, N.Y.). 2010;330(6001): 231-5. PMID: 20705812 | PMCID: PMC2967368
- Fuller B, Stukenberg P. Cell division: righting the check. Current biology : CB. 2009;19(14): R550-3. PMID: 19640489 | PMCID: PMC2880852
- Knowlton A, Vorozhko V, Lan W, Gorbsky G, Stukenberg P. ICIS and Aurora B coregulate the microtubule depolymerase Kif2a. Current biology : CB. 2009;19(9): 758-63. PMID: 19327998 | PMCID: PMC2775053
- Wan X, O'Quinn R, Pierce H, Joglekar A, Gall W, DeLuca J, Carroll C, Liu S, Yen T, McEwen B, Stukenberg P, Desai A, Salmon E. Protein architecture of the human kinetochore microtubule attachment site. Cell. 2009;137(4): 672-84. PMID: 19450515 | PMCID: PMC2699050
- Ahonen L, Kukkonen A, Pouwels J, Bolton M, Jingle C, Stukenberg P, Kallio M. Perturbation of Incenp function impedes anaphase chromatid movements and chromosomal passenger protein flux at centromeres. Chromosoma. 2008;118(1): 71-84. PMID: 18784935 | PMCID: PMC3442196
- Burke D, Stukenberg P. Linking kinetochore-microtubule binding to the spindle checkpoint. Developmental cell. 2008;14(4): 474-9. PMID: 18410725 | PMCID: PMC2696048
- Emanuele M, Lan W, Jwa M, Miller S, Chan C, Stukenberg P. Aurora B kinase and protein phosphatase 1 have opposing roles in modulating kinetochore assembly. The Journal of cell biology. 2008;181(2): 241-54. PMID: 18426974 | PMCID: PMC2315672
- Fuller B, Lampson M, Foley E, Rosasco-Nitcher S, Le K, Tobelmann P, Brautigan D, Stukenberg P, Kapoor T. Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient. Nature. 2008;453(7198): 1132-6. PMID: 18463638 | PMCID: PMC2724008
- Miller S, Johnson M, Stukenberg P. Kinetochore attachments require an interaction between unstructured tails on microtubules and Ndc80(Hec1). Current biology : CB. 2008;18(22): 1785-91. PMID: 19026542 | PMCID: PMC3145211
- Rosasco-Nitcher S, Lan W, Khorasanizadeh S, Stukenberg P. Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation. Science (New York, N.Y.). 2008;319(5862): 469-72. PMID: 18218899
- Wang W, Stukenberg P, Brautigan D. Phosphatase inhibitor-2 balances protein phosphatase 1 and aurora B kinase for chromosome segregation and cytokinesis in human retinal epithelial cells. Molecular biology of the cell. 2008;19(11): 4852-62. PMID: 18716057 | PMCID: PMC2575180
- Emanuele M, Burke D, Stukenberg P. A Hec of a microtubule attachment. Nature structural & molecular biology. 2007;14(1): 11-3. PMID: 17203069 | PMCID: 17203069
- Vorozhko V, Emanuele M, Kallio M, Stukenberg P, Gorbsky G. Multiple mechanisms of chromosome movement in vertebrate cells mediated through the Ndc80 complex and dynein/dynactin. Chromosoma. 2007;117(2): 169-79. PMID: 18057949 | PMCID: PMC2522317
- Zhang X, Lan W, Ems-McClung S, Stukenberg P, Walczak C. Aurora B phosphorylates multiple sites on mitotic centromere-associated kinesin to spatially and temporally regulate its function. Molecular biology of the cell. 2007;18(9): 3264-76. PMID: 17567953 | PMCID: PMC1951741
- Potapova T, Daum J, Pittman B, Hudson J, Jones T, Satinover D, Stukenberg P, Gorbsky G. The reversibility of mitotic exit in vertebrate cells. Nature. 2006;440(7086): 954-8. PMID: 16612388 | PMCID: PMC1513549
- Resnick T, Satinover D, MacIsaac F, Stukenberg P, Earnshaw W, Orr-Weaver T, Carmena M. INCENP and Aurora B promote meiotic sister chromatid cohesion through localization of the Shugoshin MEI-S332 in Drosophila. Developmental cell. 2006;11(1): 57-68. PMID: 16824953
- Janczyk Pawel, Skorupa KA, Tooley JG, Matson DR, Kestner CA, West T, Pornillos O, Stukenberg PT. Mechanism of Ska Recruitment by Ndc80 Complexes to Kinetochores. Developmetal Cell. 41(4): 438-449. PMCID: 28535377