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Tyrosine phosphorylation controls mitosis after all
The cell cycle is a carefully controlled process in which serine/threonine kinases play a large role. Abnormal progression or attenuation of cell cycling is implicated in the pathogenesis of various diseases, such as cancer, myocardial infarction, stroke, atherosclerosis, infection, inflammation, and neurodegenerative disorders. Caron et al. analyzed public databases for information about protein localization and tyrosine phosphorylation status in mitotic cells and devised a mitosis-associated tyrosine phosphorylation network. The extent of this network predicted that tyrosine-targeted phosphorylation plays a larger role in mitosis than previously appreciated. For example, in their network generated from data mining and in cultured cells, tyrosine phosphorylation decreased activation of Polo-like kinase 1 (PLK1), a serine/threonine kinase that promotes chromosome separation during anaphase and is often excessively abundant in cancers. The network provides a wealth of targets for exploration into cell cycle control in physiology and disease.
Abstract
Tyrosine phosphorylation is closely associated with cell proliferation. During the cell cycle, serine and threonine phosphorylation plays the leading role, and such phosphorylation events are most dynamic during the mitotic phase of the cell cycle. However, mitotic phosphotyrosine is not well characterized. Although a few functionally-relevant mitotic phosphotyrosine sites have been characterized, evidence suggests that this modification may be more prevalent than previously appreciated. Here, we examined tyrosine phosphorylation in mitotic human cells including those on spindle-associated proteins.? Database mining confirmed ~2000 mitotic phosphotyrosine sites, and network analysis revealed a number of subnetworks that were enriched in tyrosine-phosphorylated proteins, including components of the kinetochore or spindle and SRC family kinases. We identified Polo-like kinase 1 (PLK1), a major signaling hub in the spindle subnetwork, as phosphorylated at the conserved Tyr217 in the kinase domain. Substitution of Tyr217 with a phosphomimetic residue eliminated PLK1 activity in vitro and in cells. Further analysis showed that Tyr217 phosphorylation reduced the phosphorylation of Thr210 in the activation loop, a phosphorylation event necessary for PLK1 activity. Our data indicate that mitotic tyrosine phosphorylation regulated a key serine/threonine kinase hub in mitotic cells and suggested that spatially separating tyrosine phosphorylation events can reveal previously unrecognized regulatory events and complexes associated with specific structures of the cell cycle.
