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bioRxiv · 10.1101/2020.02.14.949321

Dynamic regulation of JAK-STAT signaling through the prolactin receptor predicted by computational modeling

Mortlock, R. D.·Georgia, S. K.·Finley, S. D.
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Abstract

IntroductionHormones signal through various receptors and cascades of biochemical reactions to expand beta cell mass during pregnancy. Harnessing this phenomenon to treat beta cell dysfunction requires quantitative understanding of the signaling at the molecular level. This study explores how different regulatory elements impact JAK-STAT signaling through the prolactin receptor in pancreatic beta cells. MethodsA mechanistic computational model was constructed to describe the key reactions and molecular species involved in JAK-STAT signaling in response to the hormone prolactin. The effect of including and excluding different regulatory modules in the model structure was explored through ensemble modeling. A Bayesian approach for likelihood estimation was used to parametrize the model to experimental data from the literature. ResultsReceptor upregulation, combined with either inhibition by SOCS proteins, receptor internalization, or both, was required to obtain STAT5 dynamics matching experimental results for INS-1 cells treated with prolactin. Multiple model structures could fit the experimental data, and key findings were conserved across model structures, including faster dimerization and nuclear import rates of STAT5B compared to STAT5A. The model was validated using experimental data from rat primary beta cells not used in parameter estimation. Probing the fitted, validated model revealed possible strategies to modulate STAT5 signaling. ConclusionsJAK-STAT signaling must be tightly controlled to obtain the biphasic response in STAT5 activation seen experimentally. Receptor up-regulation, combined with SOCS inhibition, receptor internalization, or both is required to match experimental data. Modulating reactions upstream in the signaling can enhance STAT5 activation to increase beta cell mass.

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Mortlock, R. D., Georgia, S. K., Finley, S. D.. 2020-02-14. Dynamic regulation of JAK-STAT signaling through the prolactin receptor predicted by computational modeling. https://doi.org/10.1101/2020.02.14.949321

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