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Rawat SJ , Araiza-Olivera D , Arias-Romero LE , Villamar-Cruz O , Prudnikova TY , Roder H , Chernoff J
H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization
Curr Biol. 2016 May 26;26(12) :1556-63
PMID: 27238285 PMCID: PMC4915977 URL: http://www.ncbi.nlm.nih.gov/pubmed/27238285
AbstractThe protein kinases Mst1 and Mst2 have tumor suppressor activity, but their mode of regulation is not well established. Mst1 and Mst2 are broadly expressed and may have certain overlapping functions in mammals, as deletions of both Mst1 and Mst2 together are required for tumorigenesis in mouse models [1-3]. These kinases act via a three-component signaling cascade comprising Mst1 and Mst2, the protein kinases Lats1 and Lats2, and the transcriptional coactivators Yap and Taz [4-6]. Mst1 and Mst2 contain C-terminal SARAH domains that mediate their homodimerization as well as heterodimerization with other SARAH domain-containing proteins, which may regulate Mst1/Mst2 activity. Here we show that, in addition to forming homodimers, Mst1 and Mst2 heterodimerize in cells, this interaction is mediated by their SARAH domains and is favored over homodimers, and these heterodimers have much-reduced protein kinase activity compared to Mst1 or Mst2 homodimers. Mst1/Mst2 heterodimerization is strongly promoted by oncogenic H-ras, and this effect requires activation of the Erk pathway. Cells lacking Mst1, in which Mst1/Mst2 heterodimers are not possible, are resistant to H-ras-mediated transformation and maintain active hippo pathway signaling compared to wild-type cells or cells lacking both Mst1 and Mst2. Our results suggest that H-ras, via an Erk-dependent mechanism, downregulates Mst1/Mst2 activity by inducing the formation of inactive Mst1/Mst2 heterodimers.
NotesRawat, Sonali J Araiza-Olivera, Daniela Arias-Romero, Luis E Villamar-Cruz, Olga Prudnikova, Tatiana Y Roder, Heinrich Chernoff, Jonathan R01 CA142928/CA/NCI NIH HHS/United States R01 CA148805/CA/NCI NIH HHS/United States R01 GM056250/GM/NIGMS NIH HHS/United States Curr Biol. 2016 May 26. pii: S0960-9822(16)30349-9. doi: 10.1016/j.cub.2016.04.027.