Nuclear to cytoplasmic shuttling of ERK promotes differentiation of muscle stem/progenitor cells

Abstract

The transition between the proliferation and differentiation of progenitor cells is a key step in organogenesis, and alterations in this process can lead to developmental disorders. The extracellular signal-regulated kinase 1/2 (ERK) signaling pathway is one of the most intensively studied signaling mechanisms that regulates both proliferation and differentiation. How a single molecule (e.g. ERK) can regulate two opposing cellular outcomes is still a mystery. Using both chick and mouse models, we shed light on the mechanism responsible for the switch from proliferation to differentiation of head muscle progenitors and implicate ERK subcellular localization. Manipulation of the fibroblast growth factor (FGF)-ERK signaling pathway in chick embryos in vitro and in vivo demonstrated that blockage of this pathway accelerated myogenic differentiation, whereas its activation diminished it. We next examined whether the spatial subcellular localization of ERK could act as a switch between proliferation (nuclear ERK) and differentiation (cytoplasmic ERK) of muscle progenitors. A myristoylated peptide that blocks importin 7-mediated ERK nuclear translocation induced robust myogenic differentiation of muscle progenitor/stem cells in both head and trunk. In the mouse, analysis of Sprouty mutant embryos revealed that increased ERK signaling suppressed both head and trunk myogenesis. Our findings, corroborated by mathematical modeling, suggest that ERK shuttling between the nucleus and the cytoplasm provides a switch-like transition between proliferation and differentiation of muscle progenitors.

Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling

“…Future work will therefore focus on the possible interactions between DUSP5 and chemical inhibitors of ERK pathway components to better inform personalized therapy. Although it is logical to test compounds already in clinical use, it will be important to also examine emerging ERK-targeted compounds that are reported to act by inhibiting ERK dimerization (47) or nuclear translocation (48), as well as explore the possibility that DUSP5-specific inhibitors may be developed. It is likely that the most effective extension of our current work will be to determine the effects of Dusp5 loss in human cancer cell lines with different oncogenic backgrounds combined with the use of murine models that allow tissue-specific conditional expression of BRAF V600E and Dusp5 deletion to further define the in vivo significance of our results.…”

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

“…Therefore, as mentioned above, for all MAPKs, the sub-cellular localization of ERK1/2 is important for their regulation and physiological functioning [4, 23, 24, 39]. Accordingly, it was shown that the nuclear accumulation of ERK1/2 upon stimulation is important primarily for the induction of proliferation, while other ERK1/2-dependent processes are mostly regulated by cytoplasmic ERK1/2 [40, 41]. It should be noted, however, that in some tissues or cells, nuclear ERK1/2 was reported to induce differentiation, including neurite outgrowth of PC12 cells [42], or development of eyes and wings in Drosophila [43, 44].…”

MCP-1-induced ERK/GSK-3β/Snail signaling facilitates the epithelial–mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells

“…51 These signaling pathways are presumed to facilitate the stability of Snail. ERK cascades are key signaling pathways involved in the regulation of multiple cellular processes, such as proliferation, 52 differentiation, 53 survival 54 and transformation. 55 The aberrant regulation of ERK signaling contributes to cancer and other human diseases.…”