RASSF5: An MST activator and tumor suppressor in vivo but opposite in vitro

• Published in: Current opinion in structural biology 2016-12, Vol.41, p.217-224
• Main Authors: Liao, Tsung-Jen, Tsai, Chung-Jung, Jang, Hyunbum, Fushman, David, Nussinov, Ruth
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle; Enzyme Activation; Humans; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Signaling System; Monomeric GTP-Binding Proteins - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2016.09.001

•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. 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.