BIOMEDICAL
ENGINEERING
SOCIETY
Cellular and Molecular Bioengineering (Ó 2020)
https://doi.org/10.1007/s12195-020-00647-8
Original Article
Dynamic Regulation of JAK-STAT Signaling Through the Prolactin
Receptor Predicted by Computational Modeling
RYLAND D. MORTLOCK
,1 SENTA K. GEORGIA,2 and STACEY D. FINLEY
1,3,4
1
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA,
USA; 2Departments of Pediatrics and Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of
Southern California, Los Angeles, CA, USA; 3Department of Biomedical Engineering, University of Southern California, Los
Angeles, CA, USA; and 4Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
(Received 19 January 2020; accepted 11 August 2020)
Associate Editor Aleksander S. Popel oversaw the review of this article
Abstract
Introduction—The expansion of insulin-producing beta cells
during pregnancy is critical to maintain glucose homeostasis
in the face of increasing insulin resistance. Prolactin receptor
(PRLR) signaling is one of the primary mediators of beta cell
expansion during pregnancy, and loss of PRLR signaling
results in reduced beta cell mass and gestational diabetes.
Harnessing the proliferative potential of prolactin signaling
to expand beta cell mass outside of the context of pregnancy
requires quantitative understanding of the signaling at the
molecular level.
Methods—A mechanistic computational model was constructed to describe prolactin-mediated JAK-STAT signaling
in pancreatic beta cells. The effect of different regulatory
modules was explored through ensemble modeling. A
Bayesian approach for likelihood estimation was used to fit
the model to experimental data from the literature.
Results—Including receptor upregulation, with either inhibition by SOCS proteins, receptor internalization, or both,
allowed the model to match experimental results for INS-1
cells treated with prolactin. The model predicts that faster
dimerization and nuclear import rates of STAT5B compared
to STAT5A can explain the higher STAT5B nuclear translocation. The model was used to predict the dose response of
STAT5B translocation in rat primary beta cells treated with
prolactin and reveal possible strategies to modulate STAT5
signaling.
Conclusions—JAK-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
Address correspondence to Stacey D. Finley, Department of
Biological Sciences, University of Southern California, Los Angeles,
CA, USA. Electronic mail: sfi
[email protected]
in the signaling can enhance STAT5 activation to increase
beta cell survival.
Keywords—Intracellular signaling, Feedback
Ensemble modeling, Beta cell biology.
control,
INTRODUCTION
Metabolic diseases impair the body’s ability to
properly convert nutrients into energy. Diabetes is a
particularly harmful metabolic disease that affects over
30 million people in the United States alone.33 While
multiple factors contribute to the pathogenesis of
diabetes, a deficit of functional insulin-secreting beta
cells underlies all forms of diabetes. In cases of Type 1
diabetes, an autoimmune attack destroys the majority
of beta cells, thus leaving patients unable to produce
insulin, the key hormone that regulates the transport
of glucose from the blood to the cells where it is used to
produce energy. Patients with Type 2 or gestational
diabetes can produce some insulin, but not enough to
properly regulate blood glucose levels in the context of
insulin resistance. Recent advances in the study of
pancreatic beta cells have shed light on the body’s
ability to adapt and expand in response to changes in
metabolic demand.36 For example, in cases of high
insulin resistance, such as pregnancy or obesity, the
body maintains glucose homeostasis by increasing beta
cell mass in the pancreas. In fact, studies have shown
that over the approximately 20-day time course of
pregnancy in mice, pancreatic beta cells both replicate
and grow in size, resulting in an increased beta cell
mass.36 The ability to induce beta cell expansion could
Ó 2020 The Author(s). This article is an open access publication
MORTLOCK et al.
be a powerful step to increase the number of functioning beta cells in diabetes patients.
Beta cell expansion is driven by signaling through
the prolactin receptor4,19,25,51 (PRLR). Signaling by
the lactogenic hormones prolactin and placental lactogen through PRLR stimulates the JAK-STAT signaling cascade.35 Specifically, Janus Kinase 2 (JAK2) is
constitutively associated with the PRLR7,17,38 and once
the JAK2 kinase is activated, it recruits and phosphorylates Signal Transducer and Activator of Transcription 5 (STAT5). STAT5 regulates the expression
of several target genes in the nucleus, including genes
related to the cell cycle20,45 and survival.21,26,50 Although initial discoveries were made in rodent models,
human prolactin has been shown to increase beta cell
survival as well.50
In this work, we investigate the mechanisms by
which the pregnancy-related hormone prolactin (PRL)
drives JAK-STAT signaling in pancreatic beta cells
using a mathematical model of the signaling pathway.
We focus our model on JAK2-STAT5 signaling that
promotes beta cell survival mediated by the protein
Bcl-xL. Experimental studies performed with the beta
cell line INS-1, as well as primary cells from rodents
and humans, demonstrate that signaling through
JAK2-STAT5 promotes cell survival via Bcl-xL.21,26
For example, Fujinaka et al. demonstrated that Bcl-xL
up-regulation induced by JAK2-STAT5 signaling
promotes beta cell survival. They demonstrated that in
both INS-1 cells and primary beta cells and showed
that siRNA knockout of Bcl-xL inhibits lactogen-mediated protection from cell death. In addition, Silva
et al.41 show that nuclear localization of STAT5 promotes Bcl-xL gene expression: they found direct
binding of STAT5 to the Bcl-xL promoter. Since beta
cell mass depends on both cell apoptosis and survival
and Bcl-xL is required to mediate pro-survival effects
in INS-1 cells and primary cells, there is a relationship
between Bcl-xL and beta cell mass.
Mathematical models have been used to elucidate
the balance between replication and apoptosis in beta
cells,30 but no molecular-detailed computational model
exists for the adaptive expansion of beta cells in
response to pregnancy. Here, we use a systems biology
approach to quantitatively analyze the beta cell
response to hormone stimulation. In particular, we use
mathematical modeling to explore the effects of various regulatory mechanisms that control signaling.
Experimental data shows that when insulin-secreting
cells of the INS-1 cell line are treated with a constant
concentration of (...truncated)
