Our Researchs
Exploring the regulation of SAC core kinases and pseudokinases in space and time
Mitosis and cell division are largely orchestrated by a set of highly conserved serine/threonine kinases, which coordinate all structural and functional aspects of the cell division machinery, including the mitotic spindle and kinetochores. These kinases include the master regulator, cyclin-dependent kinase 1 (CDK1), Polo-like kinase 1 (PLK1), Monopolar Spindle protein 1 (MPS1), the aurora kinases AurA and AurB, Budding Uninhibited by Benzimidazole 1 (BUB1) and its paralogous pseudokinase BUB1-related 1 (BUBR1). These proteins collectively coordinate the activation of mitotic centrosomes, the proper assembly of the mitotic spindle and the recruitment and activity of kinetochore proteins. How these proteins are activated in space and time, as well as the catalog of their mitotic targets, remains unknown. Several projects within the laboratory aim to deepen our understanding of the molecular mechanisms by which these kinases function.
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Identification of novel kinase signaling pathways during mitosis
Changes in phosphosignaling are thought to be particularly dynamic during mitosis, when cellular structure and organelles are almost completely reorganized in preparation for nuclear and cell division. Although the role of serine/threonine kinases during mitosis is well understood, the importance of tyrosine kinase signaling remains unclear. Tyrosine kinase signaling was generally thought to be minimal in the absence of extracellular stimulation by growth factors, and basal phosphotyrosine levels in cells are relatively low, representing less than 2% of the entire phosphoproteome. However, we have recently discovered that the basal phosphotyrosine profile in cells changes as they enter mitosis, with gains and losses of signaling becoming apparent. We are currently exploring changes in tyrosine phosphorylation during mitosis and the consequences of these changes on mitotic fidelity.
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Function and regulation of kinetochores
The kinetochore is a large, protein-rich structure that assembles on dividing chromosomes only during mitosis and serves as the primary point of attachment between the microtubules of the mitotic spindle and the dividing chromosomes. This macromolecular machinery also acts as the primary signaling center during mitosis, recruiting many of the kinases mentioned above (as well as some phosphatases!) to ensure proper and productive attachment of dividing chromosomes to the mitotic spindle. One such signaling pathway is the spindle assembly checkpoint (SAC), which monitors attachment fidelity and delays mitotic progression until these compromised attachments are corrected. Our understanding of kinetochore structure and function has advanced significantly with major discoveries by many groups in this field. However, our vision remains largely comparable to a snapshot, a frozen photograph, and we know little about the changes in the kinetochore under various conditions. We are currently studying the plasticity of this structure and the resulting functional changes in the fidelity of mitosis.
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