Figure 3.

JNK signaling in normal stem cells. (A) In embryonic stem cells (ESCs), the JNK pathway inhibits definitive endoderm (DE) differentiation and maintains the undifferentiated status. C-JUN activated by JNK1 binds transcriptional enhancers of ESC genes with OCT4, NANOG, and SMAD2/3 and maintains chromatin accessibility at the ESC stage. During the ESC-DE transition, SMAD2/3 becomes free due to decreased activity of JNK–C-JUN signaling and co-occupies DE enhancers with other DE transcriptional factors. (B) The evidence for the role of JNK signaling in iPSCs is minimal. A few conflicting reports suggest that JNK signaling is either suppressed or promoted during the reprogramming of terminally differentiated cells (e.g., fibroblasts) to iPSCs. (C) Most hematopoietic stem cells (HSCs) stay quiescent in the absence of stress, and the JNK–C-FOS/C-JUN pathway negatively controls cell cycle progression to maintain a dormant status. (D) In ISCs, the JNK signaling pathway modulates WNT signaling strength to regulate intestinal homeostasis. JNK1–C-JUN/AP-1 signaling upregulates WNT target genes, including Lgr5, Ccdn1, and Axin2, to promote proliferation and differentiation of ISCs. (E) WNT3A activates the JNK-ATF2 signaling pathway during neuronal differentiation, and ATF2 promotes neuronal gene expression.