slider-7Phosphorylation Dynamics in Cell Division

Progression through mitosis is driven by the oscillating activities of protein kinases and phosphatases that regulate most steps from mitotic entry to exit. It is the balance of these two counteracting activities that ensures mitotic fidelity. Subtle changes in substrate phosphorylation levels can lead to mitotic defects and missegregation of chromosomes, and thus aneuploidy, a hallmark of many cancers and birth defects. We are studying these phosphorylation networks to determine which changes in phosphorylation levels are linked to mitotic defects and if those lead to malignant transformation and tumorgenesis.

The human genome encodes for 518 protein kinases but only 147 protein phosphatase catalytic subunits, of which 40 dephosphorylate serine or threonine residues. To specifically oppose the action of serine/threonine kinases, protein phosphatases assemble larger holoenzyme complexes that include regulatory and scaffolding subunits in order to determine substrate specificity, holoenzyme activity, and subcellular localization. We are interested in establishing specific protein kinase – phosphatase counteractions, the mechanisms that govern phosphatase substrate specificity, and the molecular functions of substrate dephosphorylation in mitotic progression.

While the significance of protein kinases in mitosis has been clearly established and substrates of important mitotic kinases have been identified, the contribution of phosphoprotein phosphatases to mitotic phosphorylation signaling remains elusive. The function and regulation of phosphoprotein phosphatase activities, as well as specific substrates and phosphorylation sites that are targeted by these enzymes, remain for the vast part unknown. Understanding the mechanisms by which protein dephosphorylation counteracts kinase activity in mitotic progression will reveal new modes of cell cycle regulation, and potentially uncover new pathways for therapeutic intervention in cancer therapy.