MCB Accepts, published online ahead of print on 12 October 2009

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Densham, R. Articles by Olson, M. F. PubMed PubMed Citation Articles by Densham, R. Articles by Olson, M. F.

 Previous Article  |  Next Article 

Mol. Cell. Biol. doi:10.1128/MCB.00116-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

MST kinases monitor actin cytoskeletal integrity and signal via JNK stress-activated kinase to regulate p21^Waf1/Cip1 stability.

Ruth Densham, Eric O'Neill, June Munro, Ireen König, Kurt Anderson, Walter Kolch, and Michael F. Olson^*

The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow UK G61 1BD

^* To whom correspondence should be addressed. Email: m.olson{at}beatson.gla.ac.uk.

As well as providing a structural framework, the actin cytoskeleton also plays integral roles in cell death, survival and proliferation. Disruption of the actin cytoskeleton results in activation of the JNK stress-activated protein kinase (SAPK) pathway, however, the "sensor" of actin integrity that couples to the JNK pathway has not been characterized in mammalian cells. We now report that the MST kinases mediate the activation of the JNK pathway in response to disruption of the actin cytoskeleton. One consequence of actin disruption is the JNK-mediated stabilization of p21^Waf1/Cip1 (p21) via phosphorylation on Thr57. Expression of MST1 or MST2 was sufficient to stabilize p21 in a JNK- and Thr57-dependent manner, while the stabilization of p21 by actin disruption required MST-activity. These data indicate that, in addition to being components of the Salvador-Warts-Hippo tumour suppressor network and binding partners of c-Raf and the RASSF1A tumour suppressor, MST kinases serve to monitor cytoskeletal integrity and couple via the JNK SAPK pathway to the regulation of a key cell cycle regulatory protein.