MST kinases monitor actin cytoskeletal integrity and signal via c-Jun N-terminal kinase stress-activated kinase to regulate p21Waf1/Cip1 stability.

Journal article

As well as providing a structural framework, the actin cytoskeleton plays integral roles in cell death, survival, and proliferation. The disruption of the actin cytoskeleton results in the activation of the c-Jun N-terminal kinase (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 mammalian Ste20-like (MST) kinases mediate the activation of the JNK pathway in response to the disruption of the actin cytoskeleton. One consequence of actin disruption is the JNK-mediated stabilization of p21(Waf1/Cip1) (p21) via the phosphorylation of Thr57. The 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 tumor suppressor network and binding partners of c-Raf and the RASSF1A tumor 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.

Authors: Densham, R; O'Neill, E; Munro, J; König, I; Anderson, K

• Publication status: Published
• Journal: Molecular and cellular biology
• Volume: 29
• Issue: 24
• Pages: 6380-6390
• Publication date: 2009-12-01
• DOI: 10.1128/mcb.00116-09
• EISSN: 1098-5549
• ISSN: 0270-7306
• Language: English
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; Protein Synthesis Inhibitors; Animals; Protein-Serine-Threonine Kinases; NIH 3T3 Cells; RNA Interference; Enzyme Activation; Mitogen-Activated Protein Kinase 8; Humans; Emetine; Mice; Mutagenesis, Site-Directed; Actins; Cytoskeleton; Hela Cells; Recombinant Fusion Proteins; Signal Transduction; Enzyme Stability