The RAS-activated RAF→MEK→ERK MAP kinase pathway is an evolutionarily ancient signaling pathway that is critical during development and tissue homeostasis for promoting the cell division cycle leading to cell proliferation but also for terminating the cell division cycle leading to cellular differentiation [1]. However, this pathway also plays a critical role in the initiation and maintenance of a wide variety of human cancers. Experimental evidence suggests that cells are able to integrate the magnitude of ERK MAP kinase signaling over time thereby translating signal strength into disparate, and sometimes opposing, biological outcomes. Using a variety of experimental model systems [2-4] we have explored this paradigm to understand the molecular mechanisms by which this pathway may elicit cell cycle progression versus cell cycle arrest/senescence and have uncovered a potentially important role of the strength of signal pathway activation for the response of human cancer cells to pathway-targeted inhibitors.
[1] Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179-85. PMID: 7834738
[2] Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Molecular and cellular biology. 1997 Sep 1;17(9):5598-611. PMID: 9271435
[3] Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes & development. 1998 Oct 1;12(19):2997-3007. PMID: 9765202
[4] Thakur MD, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M, Stuart DD. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature. 2013 Feb 14;494(7436):251-5. PMID: 23302800