Deciphering the RAS/ERK pathway in vivo

Abstract

The RAS/ERK pathway has been intensely studied for about three decades, not least because of its role in human pathologies. ERK activation is observed in the majority of human cancers; in about one-third of them, it is driven by mutational activation of pathway components. The pathway is arguably one of the best targets for molecule-based pharmacological intervention, and several small-molecule inhibitors are in clinical use. Genetically engineered mouse models have greatly contributed to our understanding of signaling pathways in development, tissue homeostasis, and disease. In the specific case of the RAS/ERK pathway, they have revealed unique biological roles of structurally and functionally similar proteins, new kinase-independent effectors, and unsuspected relationships with other cascades. This short review summarizes the contribution of mouse models to our current understanding of the pathway.

High-speed single-molecule imaging reveals signal transduction by induced transbilayer raft phases

“…3 ), in agreement with a previous finding ( Jurianz et al, 1999 ). The signaling pathways leading to ERK activation could involve the small G-protein H-Ras, as well as Lyn ( Bertotti et al, 2006 ; Harita et al, 2008 ; Porat-Shliom et al, 2008 ; Wang et al, 2011 ; Croucher et al, 2013 ; Dorard et al, 2017 ). Therefore, we performed direct single-molecule observations of the recruitment of both Lyn kinase and H-Ras to the CD59 cluster signaling rafts.…”

“…Second, the MACC-induced CD59 clusters activate the extracellular signal-regulated kinase (ERK) signaling pathway, thus enhancing tumor cell proliferation ( Jurianz et al, 1999 ). Therefore, the basic understanding of CD59 signaling, particularly the Lyn (Src family kinase) signaling to trigger the inositol triphosphate/Ca 2+ pathway for protection against MACC binding, as well as the signaling cascades for ERK activation by way of Lyn and Ras ( Bertotti et al, 2006 ; Harita et al, 2008 ; Wang et al, 2011 ; Suzuki et al, 2012 ; Croucher et al, 2013 ; Dorard et al, 2017 ), would be useful for developing methods to regulate CD59 function, eventually leading to better therapeutic outcomes in oncology by suppressing ERK activities and reversing complement resistance ( Carter and Lieber, 2014 ).…”

An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion

“…In evolutionary terms, the paralogs RAF1 and MEK1 can be considered “moonlighting proteins,” multifunctional proteins that have evolved to carry out at least one essential function that is separate from their role within the ERK pathway. Specifically, RAF1 and MEK1 are required to regulate the activity of other pathways (RHO-dependent pathways in the case of RAF1; PI3K in the case of MEK1) via protein-protein interaction ( Desideri et al., 2015 , Dorard et al., 2017 ). Intriguingly, it is the activation of the core pathway (RAF/MEK/ERK) that generates the phosphorylated forms of RAF1 and MEK1 required for the cross-talk with the RHO and with PI3K pathway, respectively ( Varga et al., 2017 , Zmajkovicova et al., 2013 ).…”

RETRACTED ARTICLE: Ras-ERK signalling represses H1.4 phosphorylation at serine 36 to promote non-small-cell lung carcinoma cells growth and migration

“…Ras-ERK signalling has been well studied for about three decades [19]. Ras mutation and ERK activation frequently appear in the majority of human cancers, including NSCLC.…”