title: Salvador protein is a tumor suppressor effector of RASSF1A with hippo pathway-independent functions.
abstract: The RASSF1A tumor suppressor binds and activates proapoptotic MST kinases. The Salvador adaptor protein couples MST kinases to the LATS kinases to form the hippo pathway. Upon activation by RASSF1A, LATS1 phosphorylates the transcriptional regulator YAP, which binds to p73 and activates its proapoptotic effects. However, although serving as an adaptor for MST and LATS, Salvador can also bind RASSF1A. The functional role of the RASSF1A/Salvador interaction is unclear. Although Salvador is a novel tumor suppressor in Drosophila and mice, its role in human systems remains largely unknown. Here we show that Salvador promotes apoptosis in human cells and that Salvador inactivation deregulates the cell cycle and enhances the transformed phenotype. Moreover, we show that although the salvador gene is seldom mutated or epigenetically inactivated in human cancers, it is frequently down-regulated posttranscriptionally. Surprisingly, we also find that although RASSF1A requires the presence of Salvador for full apoptotic activity and to activate p73, this effect does not require a direct interaction of RASSF1A with MST kinases or the activation of the hippo pathway. Thus, we confirm a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway.
authors.affiliation: Department of Medicine, JG Brown Cancer Center, Molecular Targets Program, CTR Building, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.forename: Nadia
authors.initials: N
authors.lastname: Allen
authors.forename: Adrianna
authors.initials: A
authors.lastname: Henson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pogue
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Laura
authors.initials: L
authors.lastname: Gordon
authors.forename: Susannah
authors.initials: S
authors.lastname: Kassler
authors.forename: Thomas
authors.initials: T
authors.lastname: Dunwell
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Clark
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; C415864:SAV1 protein, human; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C456659:YY1AP1 protein, human; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases