MRC National Institute for Medical Research, London
Science for Health
Regulatory pathways involved in mitotic exit
12 April 2013
In collaboration with researchers from the USA, NIMR scientists have revealed a molecular mechanism that contributes to the release of dividing cells from mitosis. The work is published in Science.
Scaffold-assisted signalling cascades guide cellular decision-making. In budding yeast, one such signal transduction pathway known as the Mitotic Exit Network (MEN) governs the mitosis to G1 transition. The MEN is conserved across species and in metazoans is known as the Hippo tumor-suppressor pathway.
The current work by Steve Smerdon (pictured) and others now shows that signalling through the MEN kinase cascade is mediated by an unusual, two-step process. The MEN kinase Cdc15 first phosphorylates the scaffold Nud1 that, in turn, creates a phospho-docking site to which the effector kinase complex Dbf2-Mob1 binds in order to be activated by Cdc15 itself. Lasse Stach, a MRC Centenary Award Fellow in Steve Smerdon’s lab and Roksana Ogrodowicz from the Molecular Structure Division were able to crystallise and solve the structure of Mob1, a regulatory subunit of the Dbf2 kinase, in complex with a synthetic phosphopeptide mimic of the Nud1 docking motif. The structure shows that Cdc15-dependent recruitment of Dbf2-Mob1 depends on a new mode of phosphoserine recognition, adding Mob1-family proteins to an ever growing family of phospho-reader domains.
This study provides some important insights into the regulatory pathways that orchestrate the complex process of mitotic exit. Indeed, this novel mechanism of Hippo pathway activation has important implications for our understanding of signal transmission through kinase cascades as a whole and might well be telling us something about fundamental principles in scaffold-assisted signalling. It also suggests that there are many more phospho-dependent docking proteins yet to be discovered!
Steve Smerdon
Click image to view at full-size
Structure of the Mob1 protein bound to a synthetic phosphopeptide representing the Nud1 recruitment motif
Original article
Activation of the yeast Hippo pathway by phosphorylation-dependent assembly of signaling complexes
Jeremy M. Rock, Daniel Lim, Lasse Stach, Roksana W. Ogrodowicz, Jamie M. Keck, Michele H. Jones, Catherine C.L. Wong, John R. Yates III, Mark Winey, Stephen J. Smerdon, Michael B. Yaffe, Angelika Amon (2013)
Science, Epub ahead of print. Publisher abstract.
© MRC National Institute for Medical Research
The Ridgeway, Mill Hill, London NW7 1AA
Top of page