Abstract
JAK (Janus-activated kinase)-STAT (signal transducers and activators of transcription) signaling is a major signal transduction pathway in mammalian cells. Different growth factors and cytokines were reported as activators of the JAK-STAT pathway in various cell types. Interestingly, arginine-vasopressin (AVP) was never reported as an inducer of the JAK-STAT pathway. In the present study, we show for the first time that AVP stimulation of vascular smooth muscle cells (VSMCs) induces STAT3 tyrosine and serine phosphorylation, followed by nuclear translocation of the phosphorylated STAT3. In addition, we found that AVP induced JAK2 tyrosine phosphorylation. Taken together, these results demonstrate that AVP activates the JAK-STAT pathway in VSMCs. Furthermore, our results indicate that AVP-induced STAT3 tyrosine phosphorylation requires both JAK2 and c-Src tyrosine kinases. The present study also implicates that extracellular signal-regulated kinase (ERK1/2), which are serine/threonine kinases, are the mediators of STAT3 serine phosphorylation upon AVP stimulation. We further suggest that AVP-induced STAT3 serine phosphorylation negatively modulates AVP-induced STAT3 tyrosine phosphorylation. Finally, our results implicate a novel role for the JAK-STAT pathway, mediating AVP-induced VSMC hypertrophy.
Highlights
As in other cell types, the JAK-STAT pathway has a major role in vascular smooth muscle cells (VSMCs)
Arginine vasopressin (AVP) was never reported as an activator of the JAK-STAT pathway
As previously described the JAK-STAT pathway is activated by various cytokines and growth factors, such as platelet derived growth factor (PDGF), epidermal growth factor (EGF), interleukin-6, and angiotensin II (AngII) [5,6,7,8, 33]
Summary
As in other cell types, the JAK-STAT pathway has a major role in VSMCs. The abundant isoforms in VSMCs are STAT1, STAT3, and JAK2. It was previously described that GPCRs-induced tyrosine phosphorylation and activation of STAT proteins appears to require the JAK family of tyrosine kinases [10]. Treatment with SB203580 (10 M, for 30 min prior to AVP stimulation), which is a specific p38 MAPK inhibitor [26], had no significant effect on STAT3 serine phosphorylation indicating that p38 MAPK is not responsible for AVP-induced STAT3 serine phosphorylation (Fig. 6E).
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