JAK/STAT signalling mediates cell survival in response to tissue stress

Abstract

Tissue homeostasis relies on the ability of tissues to respond to stress. Tissue regeneration and tumour models in Drosophila have shown that c-Jun amino-terminal kinase (JNK) acts as a prominent stress-response pathway promoting injury-induced apoptosis and compensatory proliferation. A central question remaining unanswered is how both responses are balanced by activation of a single pathway. Signalling through the Janus kinase/Signal transducers and activators of transcription (JAK/STAT) pathway, which is a potential JNK target, is implicated in promoting compensatory proliferation. While we observe JAK/STAT activation in imaginal discs upon damage, our data demonstrate that JAK/STAT and its downstream effector Zfh2 promote the survival of JNK signalling cells. The JNK component fos and the pro-apoptotic gene hid are regulated in a JAK/STAT-dependent manner. This molecular pathway restrains JNK-induced apoptosis and spatial propagation of JNK signalling, thereby limiting the extent of tissue damage, as well as facilitating systemic and proliferative responses to injury. We find that the pro-survival function of JAK/STAT also drives tumour growth under conditions of chronic stress. Our study defines the function of JAK/STAT in tissue stress and illustrates how crosstalk between conserved signalling pathways establishes an intricate equilibrium between proliferation, apoptosis and survival to restore tissue homeostasis.

Survival/Adaptation of Bone Marrow-Derived Mesenchymal Stem Cells After Long-Term Starvation Through Selective Processes

“…Among the modulated pathways analyzed, we found Jak/Stat. This pathway has been shown to mediate different responses to various forms of biological stress, including hypoxia/reperfusion, endotoxin, ultraviolet light, and hyperosmolarity . Our results demonstrated pSTAT6 was highly active during starvation and was downregulated after the medium change, suggesting a direct relationship between its activation and the hyperosmotic and hypoxic conditions created during starvation.…”

JNK signaling in cancer cell survival

“…Recent studies further showed that some signals including JAK/STAT and β‐catenin/TCF are required to facilitate the JNK‐dependent compensatory cell proliferation . The JNK component fos and the proapoptotic gene hid are regulated in a JAK/STAT‐dependent manner . The JAK/STAT pathway suppresses JNK signaling and restrains the JNK‐induced cell apoptosis.…”

JAK/STAT signaling in stem cells and regeneration: fromDrosophilato vertebrates

“…Activation of JNK and p38 in surviving cells induces Upd ligands, particularly Upd3 (Ahmed- de-Prado et al, 2018;Katsuyama et al, 2015;Klebes et al, 2005;La Fortezza et al, 2016;Pastor-Pareja et al, 2008;Santabárbara-Ruiz et al, 2015;Worley et al, 2018). Notably, one study found that the same 4 kb upd3 enhancer induced in the Drosophila gut in response to damage was also induced in the wing disc during regeneration (Worley et al, 2018), indicating that Upd production in response to inflammation is a common feature in intestinal and appendage regeneration.…”