Raymond L. Erikson
Department of Molecular & Cellular Biology
Reversible protein phosphorylation and cell proliferation.Our studies focus on the role of reversible phosphorylation in the regulation of essential steps in cell proliferation. Recently we have focused on the functions and regulation of polo-like kinases (Plk) in mammalian cells. Three mammalian Plks have been identified; Plk1 is expressed during M phase and cytokinesis, whereas Plk2 (Snk) and Plk3 (Fnk) are expressed in other phases of the cell cycle. These enzymes are characterized by their similar N-terminal catalytic domains, as well as a C-terminal domain with highly conserved sequences termed the polo box. We have previously demonstrated that the polo box directs Plk1 to specific cellular locations and is required together with protein kinase activity to promote cell proliferation. Plk1 localizes to centrosomes and the spindle poles at metaphase, in the central spindle during anaphase, and at the midbody during cytokinesis. Plk1 has been implicated in centrosome maturation, bipolar spindle formation and activation of the anaphase-promoting complex.
We have determined that intramolecular interactions of the catalytic and non-catalytic domains, as well as phosphorylation of Plk1 regulate the activation of its protein kinase activity. Our use of small interfering RNA to deplete Plk1 in cells demonstrates that it is required for centrosome duplication, anaphase and cytokinesis in mammalian cells. Cancer cells depleted of Plk1 rapidly undergo apoptosis. We are investigating whether this occurs in a wide variety of tumor cells or normal cells, as Plk1 may be a useful chemotherapy target.
A major effort in our laboratory is directed at identification and characterization of Plk1 substrates. Mitotic motor proteins, including the mitotic kinesin-like protein (MKLP1/CHO1), are of special interest. We also study the changes in function of substrates after mutation of sites phosphorylated by Plk1.
Ma, S., Liu, M. A., Yuan, Y. L., and Erikson, R. L. (2003). The serum-inducible protein kinase Snk is a G(1) phase polo-like kinase that is inhibited by the calcium- and integrin-binding protein CIB. Mol Cancer Res 5, 376-84.
Liu, X. and Erikson, R.L. (2003) Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci USA 100, 5789-5794.
Bélanger, L-F., Roy, S., Tremblay, M., Brott, B., Steff, A-M., Mourad, W., Hugo, P., Erikson, R. L., and Charron, J. (2003). MEK2 is dispensable for mouse growth and development. Mol Cell Biol 23(14), 4778-4787.
Zhou, T., Aumais, J., Liu, X., Yu-Lee, L. Y., and Erikson, R. L. (2003) A role for Plk1 phosphorylation of NudC in cytokinesis. Developmental Cell 5, 127-138.
Ma, S., Charron, J., and Erikson, R.L. (2003). The role of Plk2 (Snk) in mouse development and cell proliferation. Mol Cell Biol (in press).
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