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.

Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

“…5E-F, Additional file S3). Genes upregulated in ZWf embryos compared to ZZf embryos included STAT1 , a component of the JAK-STAT pathway, with several roles in stress responses (62), and MAP3K1 and MAPK8 , which are typically involved in mediating stress-related signal transduction cascades (63–65). TERF2IP is also upregulated; this gene is involved in telomere length maintenance and transcription regulation (66).…”

JNK signaling in cancer cell survival

“…50,132 The JNK component fos and the proapoptotic gene hid are regulated in a JAK/STAT-dependent manner. 133 The microvesicles, which induce the proliferation of neighboring cells, and this process requires JNK activity. 136 The mTOR pathway mediates beta cell compensatory proliferation in mice with a partial (60%) pancreatectomy, indicating that autophagy may be involved in this process.…”

Regenerative capacity inDrosophilaimaginal discs is controlled by damage-responsive, maturity-silenced enhancers

“…However, we cannot exclude the possibility that other mechanisms might be more important. A previous study has shown that reducing JAK/STAT signaling reduced tissue loss following egr-induced ablation, but did not seem to compromise the extent of compensatory proliferation (La Fortezza et al, 2016).…”

“…The 1458 genes that are closest to the 729 MS peaks represent 1143 unique genes, with individual genes being associated with 1-8 peaks ( Supplemental table 6). In addition to the Wnt pathway, the JAK/STAT pathway (Katsuyama et al, 2015;La Fortezza et al, 2016) and the Hippo pathway (Grusche et al, 2011;Sun and Irvine, 2011) have been shown to be required for regeneration in imaginal discs. Moreover, we have previously shown that the activity of each of these two pathways is markedly different in early and late L3 discs following damage (Harris et al, 2016).…”