Weiwen Long, Ph.D. (Advisor); Madhavi Kadakia, Ph.D. (Committee Member); Hongmei Ren, Ph.D. (Committee Member)
Master of Science (MS)
Mitogen activated protein kinases (MAPKs) are Ser/Thr kinases that relay the extracellular signal into intracellular responses and regulate several biological responses. They are classified into conventional MAPKs and atypical MAPKs. Extracellular signal regulated kinase 3 (ERK3) is an atypical MAPK that has a single phospho-acceptor site (Ser 189) in its activation motif instead of the canonical Thr-Xaa-Tyr (TXY) motif of conventional MAPK like ERK1/2. ERK3 comprises of a unique C terminal tail and a central C34 domain that further distinguishes it from ERK1/2. Moreover, compared to ERK1/2, much less is known about the upstream activators and the downstream targets of ERK3. Here, our study identifies IL-6 signaling to be negatively regulated by ERK3. We show that ERK3 downregulates the IL-6 target genes and STAT3 phosphorylation. IL-6 is a multifunctional pleiotropic cytokine that signals predominantly via JAK/STAT signaling pathway. In response to IL-6, STAT3 is phosphorylated at Tyrosine 705 (Y705) residue by JAK2, which successively activates STAT3 as a transcription factor. The IL-6/STAT3 pathway is negatively regulated by a feedback inhibitor SOCS3 (Suppressor of Cytokine Signaling 3) which binds to JAK2, hence, preventing the phosphorylation and activation of STAT3. Interestingly, this study reveals that ERK3 interacts with SOCS3 via its C34 domain. Until now, there has been no information about the physiological or the biochemical function of the C34 domain of ERK3. Hence this study has identified a novel role of ERK3’s C34 domain. Furthermore, we show that ERK3 facilitates the interaction between SOCS3 and JAK2, promoting the inhibition of STAT3 Y705 phosphorylation and activation. Taken together, the findings of our study provide important and novel insights into the negative regulation of IL-6/STAT3 signaling pathway by ERK3.
Year Degree Awarded
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