Though JAK/STAT signaling pathway play an important role in many regulation process, the pathway has been well conserved during evolution from flies to humans. Just as is reported in existing studies, the human JAK/STAT transduces various pro-proliferation and anti-apoptotic signals from numerous hematopoietic cytokines and growth factors, and at last leads to corresponding changes in target gene expression. Under the stimulation from the external environment and regulation by the cell itself, consequent disorder of the JAK/STAT pathway will be followed by several pathological conditions, including cancer; myeloproliferative neoplasms; serious immune deficiencies, such as severe combined immune deficiency; allergies; and autoimmunity diseases. Thus, some agents, Tasocitinib and INCB018424, have been used in the treatment of diseases above.
Then, the story about regulation occurs among 4 JAKs and 7 different STATs for humans. However, for the fruit fly Drosophila melanogaster, the JAK/STAT pathway only consists of only one cytokine receptor-like transmembrane protein, domeless (Dome); one JAK, termed hopscotch (Hop); and a single Stat92E. Beside the control of immune and stress responses, JAK/STAT also contributes to developmental events in Drosophila. Just like in human, the JAK/STAT pathway is closely regulated. For example, in Drosophila, Socs36E has been found to participate in JAK/STAT pathway regulation in a similar manner with human SOCSs. In a recent study, eye transformer (ET), a novel negative regulator of the Drosophila JAK/STAT pathway, was identified in a genome-wide RNAi screen.
According to the findings, Gronholm et al. also reported their study results on another novel regulator of the JAK/STAT pathway, CG31716, which encodes the Drosophila Not4 protein. As expected, CG31716/Not4 is confirmed to positively regulate Drosophila JAK/STAT pathway in S2 cells, for overexpression of Not4 can activate Stat92E-dependent reporter gene expression. In the following in vivo assay, overexpression of Not4 also shows the similar effects on JAK/STAT pathways. As we described in the opening, many regulators of the JAK/STAT signaling pathway have been conserved in evolution, and human CNOT4 is homologue of Drosophila Not4. CNOT4 positively regulates JAK/STAT signaling in human cells, which suggests the accuracy of the above results. In addition, further analysis on Not4 structure indicates that Not4-mediated regulation of the Drosophila JAK/STAT pathway is independent of the RING and the RRM domains. About the action mechanism, Drosophila Not4 is observed to enhance DNA binding ability of Stat92E with no significant effect on Stat92E tyrosine phosphorylation.
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In summary, Not4, as a novel positive regulator of the JAK/STAT pathway plays the important role both in vitro and in vivo in Drosophila, so does the homologue CNOT4 in human cells. Though existing studies have suggested Not4 may contribute to regulation of Stat92E by affecting Stat92E DNA binding ability, the concrete needs further study.
. FASEB J. 2012; 26, 000–000. doi: 10.1096/fj.11-195875.
CUEDC2, an inhibitor of JAK1/STAT3 signaling
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