title: RASSF5: An MST activator and tumor suppressor in vivo but opposite in vitro.
abstract: Is RASSF5 a tumor suppressor or activator? RASSF5 links K-Ras and the Hippo pathway. Hippo's signaling promotes YAP1 phosphorylation and degradation. YAP1 overexpression promotes cancer. Most reports point to RASSF5 suppressing cancer; however, some point to its promoting cancer. Our mechanistic view explains how RASSF5 can activate MST1/2 and suppress cancer in vivo; but inhibits MST1/2 in vitro. We propose that both activation and inhibition of MST1/2 can take place via SARAH heterodimerization. Our thesis in vivo, membrane-anchored Ras dimers (or nanoclusters) can promote SARAH domain heterodimerization, Raf-like MST1/2 kinase domain homodimerization and trans-autophosphorylation. In contrast, in vitro, K-Ras binding also releases the RASSF5 SARAH stimulating MST1/2's SARAH heterodimerization; however, without membrane, no MST1/2 kinase domain homodimerization/trans-autophosphorylation.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Biophysics Program, University of Maryland, College Park, MD 20742, USA.
authors.forename: Tsung-Jen
authors.initials: TJ
authors.lastname: Liao
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Biophysics Program, University of Maryland, College Park, MD 20742, USA; Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD 20742, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fushman
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: nussinor@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D000818:Animals; D002453:Cell Cycle; D004789:Enzyme Activation; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D020930:MAP Kinase Kinase Kinases; D020559:Monomeric GTP-Binding Proteins