P. Todd Stukenberg

Education

  • Postdoc, Harvard Medical School
  • PhD, Sloan-Kettering Cancer Institute, and Cornell Medical School, NY, NY.

Primary Appointment

  • Professor, Biochemistry and Molecular Genetics

Contact

Research Interest(s)

Mechanisms of chromosome segregation, cytokinesis and generation of aneuploidy

Research Description

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 Publications

  • 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
  • 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
  • Beum P, Lindorfer M, Peek E, Stukenberg P, de Weers M, Beurskens F, Parren P, van de Winkel J, Taylor R. Penetration of antibody-opsonized cells by the membrane attack complex of complement promotes Ca(2+) influx and induces streamers. European journal of immunology. 2011;41(8): 2436-46. PMID: 21674476
  • 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
  • Beum P, Lindorfer M, Beurskens F, Stukenberg P, Lokhorst H, Pawluczkowycz A, Parren P, van de Winkel J, Taylor R. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. Journal of immunology (Baltimore, Md. : 1950). 2008;181(1): 822-32. PMID: 18566448
  • 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
  • Momotani K, Khromov A, Miyake T, Stukenberg P, Somlyo A. Cep57, a multidomain protein with unique microtubule and centrosomal localization domains. The Biochemical journal. 2008;412(2): 265-73. PMID: 18294141
  • 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
  • Emanuele M, Stukenberg P. Xenopus Cep57 is a novel kinetochore component involved in microtubule attachment. Cell. 2007;130(5): 893-905. PMID: 17803911
  • Li L, Yang L, Scudiero D, Miller S, Yu Z, Stukenberg P, Shoemaker R, Kotin R. Development of recombinant adeno-associated virus vectors carrying small interfering RNA (shHec1)-mediated depletion of kinetochore Hec1 protein in tumor cells. Gene therapy. 2007;14(10): 814-27. PMID: 17330085
  • Li M, Stukenberg P, Brautigan D. Binding of phosphatase inhibitor-2 to prolyl isomerase Pin1 modifies specificity for mitotic phosphoproteins. Biochemistry. 2007;47(1): 292-300. PMID: 18062707
  • 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
  • Wang R, He G, Nelman-Gonzalez M, Ashorn C, Gallick G, Stukenberg P, Kirschner M, Kuang J. Regulation of Cdc25C by ERK-MAP kinases during the G2/M transition. Cell. 2007;128(6): 1119-32. PMID: 17382881
  • 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
  • Knowlton A, Lan W, Stukenberg P. Aurora B is enriched at merotelic attachment sites, where it regulates MCAK. Current biology : CB. 2006;16(17): 1705-10. PMID: 16950107
  • 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
  • Satinover D, Brautigan D, Stukenberg P. Aurora-A kinase and inhibitor-2 regulate the cyclin threshold for mitotic entry in Xenopus early embryonic cell cycles. Cell cycle (Georgetown, Tex.). 2006;5(19): 2268-74. PMID: 16969136