Tuning In: How Erk Dynamics Influence Downstream Gene Expression in Mouse Keratinocytes

Abstract

The Ras/Erk mitogen-activated protein kinase (MAPK) pathway is a central signaling pathway that is involved in diverse cell fates such as proliferation, differentiation, and apoptosis. Although the molecular players of the pathway have been extensively characterized, the method by which the cell uses a single pathway to interpret varying inputs into different downstream outputs is still unknown. Uncovering this missing process of regulation is crucial for understanding not only natural phenomena, but also pathogenic cellular behavior, as mutations in the Ras/Erk pathway account for nearly a third of all cancers and 80% of melanomas. Our lab is interested in one dimension of control—dynamics of Erk activity. Changes in Erk oscillations in cells have shown to result in different downstream cellular outcomes, but whether and how these oscillations inform transcription of downstream gene targets remains an open question. Primary mouse keratinocyte epithelial cells display endogenous pulsatile Erk activity and exhibit strong proliferation and differentiation behaviors, making them an ideal candidate for studying the significance of Erk dynamics. In my thesis work, I built a system for live-cell reporting of pulsatile Erk activity and transcriptional activity of the immediate-early gene Fos in mouse keratinocytes. My findings show that Erk oscillations, whether intrinsic or environmentally induced, lead to transcriptional activity of the Fos promoter. Moreover, drugs that target the Ras/Erk pathway induce changes in pulsatile Erk activity that is carried through in transcriptional changes. My findings expand on the role of Erk dynamics in determining downstream cell-fates, and my project provides promising future directions for continued exploration of signaling dynamics in keratinocytes.