Hu, W., Liu, H., Lin, L., Li, M., Fan, Z., Zhang, Y., Lin, X., Qi, Y. (2025). Feedback inhibition of the Janus kinase/signal transducer and activator of transcription signaling pathway by CG5953 through Ptp61F.  Int. J. Biol. Macromol. 330(1): 147875.

FBrf0263806

Research paper

The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway is evolutionarily conserved, and its regulatory mechanisms are believed to be preserved across species. However, our current understanding of its feedback regulation remains poorly understood. Utilizing Drosophila melanogaster model, we have recently identified some potent feedback regulators of JAK/STAT signaling, but the underlying molecular mechanisms remain elusive. Here we report CG5953. The expression of CG5953 exhibits a robust response to JAK/STAT activation within the adult Drosophila midgut. Overexpression of CG5953 significantly impedes the activity of JAK/STAT signaling. Mechanistically, the nuclear localization of CG5953 is imperative for its regulation of the JAK/STAT signaling, which is achieved through the reduction of phospho-STAT92E levels. Furthermore, CG5953 engages in interactions with STAT92E and Ptp61F, the human counterpart of which is the nuclear non-receptor protein tyrosine phosphatase PTPN2. Depletion of ptp61F significantly disrupts the inhibitory effect of CG5953 on the JAK/STAT signaling. Consequently, CG5953 functions as an adaptor protein to facilitate the dephosphorylation of phospho-STAT92E by Ptp61F. Our findings may offer valuable insights into the mechanisms underlying the targeting of JAK/STAT signaling by nuclear non-receptor protein tyrosine phosphatases.