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Abstract MAPK signaling modules play crucial roles in regulating numerous biological processes in all eukaryotic cells. How MAPK signaling specificity and strength are tightly controlled remains a major challenging question. InArabidopsisstomatal development, the MAPKK Kinase YODA (YDA) functions at the cell periphery to inhibit stomatal production by activating MAPK 3 and 6 (MPK3/6) that directly phosphorylate stomatal fate-determining transcription factors for degradation in the nucleus. Recently, we demonstrated that BSL1, one of the four BSL protein phosphatases, localizes to the cell cortex to activate YDA, elevating MPK3/6 activity to suppress stomatal formation. Here, we showed that at the plasma membrane, all four members of BSL proteins contribute to the YDA activation. However, in the nucleus, specific BSL members (BSL2, BSL3, and BSU1) directly deactivate MPK6 to counteract the linear MAPK pathway, thereby promoting stomatal formation. Thus, the pivotal MAPK signaling in stomatal fate determination is spatially modulated by a signaling dichotomy of the BSL protein phosphatases inArabidopsis, providing a prominent example of how MAPK activities are integrated and specified by signaling compartmentalization at the subcellular level.
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This content will become publicly available on September 1, 2026
Chemogenetic tuning reveals optimal MAPK signaling for cell-fate programming
Cell states evolve through the combined activity of signaling pathways and gene networks. While transcription factors can direct cell fate, these factors rely on a receptive cell state. How signaling levels contribute to the emergence of receptive cell states remains poorly defined. Using a well-defined model of direct conversion, we examined how levels of the mitogen-activated protein kinase (MAPK)-activating oncogene HRASG12V influence direct conversion of primary fibroblasts to induced motor neurons. The rates of direct conversion respond biphasically to increasing HRASG12V levels. An optimal “Goldilocks” level of MAPK signaling efficiently drives cell-fate programming, whereas high levels of HRASG12V induce senescence. Through chemogenetic tuning, we set the optimal MAPK activity for high rates of conversion in the absence of HRAS mutants. In addition to proliferation, MAPK signaling influences conversion by regulating Ngn2 activity. Our results highlight the need to tune therapeutic interventions within a non-monotonic landscape that is shaped by genetics and levels of gene expression.
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- Award ID(s):
- 2339986
- PAR ID:
- 10651991
- Publisher / Repository:
- Cell Reports
- Date Published:
- Journal Name:
- Cell Reports
- Volume:
- 44
- Issue:
- 9
- ISSN:
- 2211-1247
- Page Range / eLocation ID:
- 116226
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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