title: H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization.
abstract: The 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.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Sonali J
authors.initials: SJ
authors.lastname: Rawat
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Araiza-Olivera
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, México.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Arias-Romero
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, México.
authors.forename: Olga
authors.initials: O
authors.lastname: Villamar-Cruz
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Prudnikova
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Roder
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: j_chernoff@fccc.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D011905:Genes, ras; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D000099317:Hippo Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C095566:STK4 protein, human; D000099317:Hippo Kinases; C097835:STK3 protein, human