RASSF5: An MST activator and tumor suppressor in vivo but opposite in vitro. (December 2016)

• Record Type: Journal Article
• Authors: Liao, Tsung-Jen; Tsai, Chung-Jung; Jang, Hyunbum; Fushman, David; Nussinov, Ruth
• Is Part Of: Current opinion in structural biology. Volume 41(2016)
• Page Start: 217
• Page End: 224
• Publication Date: 2016-12
• Subjects: Molecular biology -- Periodicals; 570
• DOI: 10.1016/j.sbi.2016.09.001
• Languages: English
• ISSNs: 0959-440X

Abstract

Highlights: RASSF5 links Ras and the Hippo pathway whose signaling leads to YAP degradation. YAP1 overexpression promotes cancer. Most reports point to RASSF5 suppressing cancer; however, some to promoting cancer. We propose that RASSF5 acts as an adaptor protein. RASSF5 activates MST and suppress cancer in vivo ; but inhibit signaling 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.