"Switches and Latches: The Control of Entry into Mitosis" Prof Tim Hunt

Switches and Latches: The Control of Entry into Mitosis

Tim Hunt

Cancer Research UK, London Research Institute, Clare Hall Laboratories,
South Mimms, Herts EN6 3LD, U.K.

The process of mitosis involves a comprehensive reorganization of the cell: chromosomes condense, the nuclear envelope breaks down, the mitotic spindle is assembled, cells round up and release their ties to the substrate and so on and so forth. This reorganization is triggered by the activation of the protein kinase, Cyclin-Dependent Kinase 1 (CDK1). The end of mitosis is marked by the proteolysis of the cyclin subunit of CDK1, which terminates kinase activity. At this point, the phosphate moieties that altered the properties of hundreds of proteins to bring about the cellular reorganization are removed by protein phosphatases. We recently began to pay attention to the control of these enzymes, considering it likely that they were shut off as cells enter mitosis, and reactivated when mitosis is complete, to allow the return to interphase.

And it turned out indeed that (at least) one protein phosphatase, PP2A-B55, is completely shut off in mitosis. Depletion of this particular form of PP2A accelerated entry into mitosis, and blocked exit from mitosis. Control of this enzyme is achieved by an inhibitor protein (α-endosulfine or ARPP-19) that becomes inhibitory when phosphorylated by a protein kinase called Greatwall, which is itself a substrate of CDK1. Failure to inhibit PP2A-B55 causes arrest of the cell cycle in G2 phase. I will discuss the role of this control mechanism in the control of mitosis. We still have a rather incomplete understanding of exactly how the timing of entry into mitosis is controlled. There are also a number of puzzles about the precise role of PP2A-B55 in the process of exit from mitosis, with different approaches giving confusingly different results. Finally, although the inhibitory mechanism we have uncovered is clearly very important in frog and fly eggs and early embryos, there are organisms such as yeast and nematodes where such is not the case. Further experiments are needed to unravel these puzzles.