title: MEK1-RSK2 contributes to Hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination.
abstract: The transcription factor GLI2 has an important role in the transduction of Hedgehog signaling and thereby regulates tumorigenesis in a wide variety of human tumors. However, the mechanisms controlling GLI2 protein expression and stabilization are incompletely understood. In this study, we show that the mitogen-activated protein kinase MEK1 modulates GLI2 both at the mRNA and protein level. Constitutively activated MEK1 prolonged the half-life of GLI2 and increased its nuclear translocation, accompanied by attenuated ubiquitination of GLI2 protein. RSK2, a protein kinase lying downstream of MEK-ERK cascade, mimicked the effect of MEK on GLI2 stabilization. MEK1 and RSK2 failed to augment the half-life of GLI2 lacking GSK-3β phosphorylation sites, indicating that MEK-RSK stabilizes GLI2 by controlling targeting GSK-3β-mediated phosphorylation and ubiquitination of GLI2. The significance of MEK-RSK stabilization was demonstrated in experiments showing that activation of MEK-RSK paralleled higher protein level of GLI2 in several multiple myelomas (MM) cells relative to normal B cells. Moreover, combined treatment with RSK and GLI inhibitors led to an enhanced apoptosis of MM cells. Thus, our results indicate that MEK-RSK cascade positively regulates GLI2 stabilization and represses its degradation via inhibiting GSK-3β-dependent phosphorylation and ubiquitination of GLI2.
authors.affiliation: 1] Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, China.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: 1] Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Physician Assistant Studies, Grand Valley State University, Grand Rapids, MI, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Reinhold
authors.affiliation: 1] Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Pathology, St Mary's Health Care, Grand Rapids, MI, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Naski
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D045744:Cell Line, Tumor; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006207:Half-Life; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D055550:Protein Stability; D059748:Proteolysis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000075746:Zinc Finger Protein Gli2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D038362:Glycogen Synthase Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human