Overview
Mitotic commitment control from the fission yeast spindle pole body
The observation that active CDK1-Cyclin B appears on human centrosomes before propagating throughout the cell has been consolidated by other data to suggest that the centrosome provides a specific microenvironment for the activation of CDK1-Cyclin B to trigger the G2/M transition. Our studies of the fission yeast centrosome equivalent, the spindle pole body (SPB), provide molecular insight into how this switch may operate. Simply blocking the recruitment of protein phosphatase 1 (PP1) to the SPB scaffold Cut12 enables cells to live without Cdc25. Furthermore, PP1 eviction from Cut12 is the only essential function for Cdk1-CyclinBCdc13 in driving cells into division. The means by which the Cut12/PP1 switch regulates mitotic commitment appears to involve the mitotic kinase Polo, as Polo activity and recruitment to the SPB shows a direct, inverse correlation with PP1 recruitment to the SPB, and artificial elevation of Polo activity at the SPB drives cells into division. As Polo kinase activity is regulated by nutritional status and stress responses, Polo kinase engagement in this switch couples division timing to the specific demands of any given environmental context.
The threshold for Cut12 signalling that must be passed before the cell enters division is set by a signalling relay on a neighbouring scaffold molecule, Sid4. This relay regulates the SPB residence of a Cdk1-Cyclin B counteracting phosphatase called Cdc14Flp1. Thus, it is the dialogue between Cut12 and Sid4 that determines when division will be initiated. Sid4 also anchors the cytokinesis regulating Septum Initiation Network to the SPB. This anchorage is essential to ensure the SIN signalling can drive the events of mitotic exit and cytokinesis. Thus, signalling from these two neighbouring SPB signalling platforms acts like the central processing unit of a computer. Converging signals from multiple pathways are integrated to generate a coherent signal that sets the flux through outgoing signalling cascades that tells the cell when to enter and exit mitosis. We are currently seeking the mechanistic basis for Polo and Cdc14Flp1 engagement in these networks and the function of similar centrosomal scaffolds in human cells.
