The intricate dynamic control and plasticity of RAS to ERK mitogenic, survival and apoptotic signalling has mystified researches for more than 30 years. Therapeutics targeting the oncogenic aberrations within this pathway often yield unsatisfactory, even undesired results, as in the case of paradoxical ERK activation in response to RAF inhibition. A direct approach of inhibiting single oncogenic proteins misses the dynamic network context governing the network signal processing. In this review, we discuss the signalling behaviour of RAS and RAF proteins in normal and in cancer cells, and the emerging systems-level properties of the RAS-to-ERK signalling network. We argue that to understand the dynamic complexities of this control system, mathematical models including mechanistic detail are required. Looking into the future, these dynamic models will build the foundation upon which more effective, rational approaches to cancer therapy will be developed.
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Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer.
Cell Mol Life Sci
September 2022
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), 28029, Madrid, Spain.
Background: RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo.
Methods: We used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics.
Lighting Up Cancer Dynamics.
Trends Cancer
October 2018
Department of Molecular, Cellular, and Developmental Biology, University of California-Santa Barbara, Santa Barbara, CA 93106, USA. Electronic address:
Live-cell microscopy has revealed that signaling pathways carry elaborate time-varying activities. Yet, the connection between these dynamics and cellular disease has remained elusive. Recent work leverages cellular optogenetics to analyze the Ras-to-Erk transfer function in cancer cells.
View Article and Find Full Text PDFExtracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes.
Adv Cancer Res
September 2019
Medical University of South Carolina, Charleston, SC, United States. Electronic address:
The extracellular-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that are involved in regulating cellular signaling in both normal and pathological conditions. Their expression is critical for development and their hyperactivation is a major factor in cancer development and progression. Since their discovery as one of the major signaling mediators activated by mitogens and Ras mutation, we have learned much about their regulation, including their activation, binding partners and substrates.
View Article and Find Full Text PDFRAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKα.
Sci Signal
March 2017
Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Downstream of growth factor receptors and of the guanine triphosphatase (GTPase) RAS, heterodimers of the serine/threonine kinases BRAF and RAF1 are critical upstream kinases and activators of the mitogen-activated protein kinase (MAPK) module containing the mitogen-activated and extracellular signal-regulated kinase kinase (MEK) and their targets, the extracellular signal-regulated kinase (ERK) family. Either direct or scaffold protein-mediated interactions among the components of the ERK module (the MAPKKKs BRAF and RAF1, MEK, and ERK) facilitate signal transmission. RAF1 also has essential functions in the control of tumorigenesis and migration that are mediated through its interaction with the kinase ROKα, an effector of the GTPase RHO and regulator of cytoskeletal rearrangements.
View Article and Find Full Text PDFThe complexities and versatility of the RAS-to-ERK signalling system in normal and cancer cells.
Semin Cell Dev Biol
October 2016
Systems Biology Ireland, UCD School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address:
The intricate dynamic control and plasticity of RAS to ERK mitogenic, survival and apoptotic signalling has mystified researches for more than 30 years. Therapeutics targeting the oncogenic aberrations within this pathway often yield unsatisfactory, even undesired results, as in the case of paradoxical ERK activation in response to RAF inhibition. A direct approach of inhibiting single oncogenic proteins misses the dynamic network context governing the network signal processing.
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