Phosphatases are predicted to govern prolactin-mediated JAK–STAT signaling in pancreatic beta cells

Author:

Simoni Ariella D1,Huber Holly A1,Georgia Senta K2,Finley Stacey D134ORCID

Affiliation:

1. Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA

2. Departments of Pediatrics and Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

3. Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA

4. Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA

Abstract

Abstract Patients with diabetes are unable to produce a sufficient amount of insulin to properly regulate their blood glucose levels. One potential method of treating diabetes is to increase the number of insulin-secreting beta cells in the pancreas to enhance insulin secretion. It is known that during pregnancy, pancreatic beta cells proliferate in response to the pregnancy hormone, prolactin (PRL). Leveraging this proliferative response to PRL may be a strategy to restore endogenous insulin production for patients with diabetes. To investigate this potential treatment, we previously developed a computational model to represent the PRL-mediated JAK–STAT signaling pathway in pancreatic beta cells. Here, we applied the model to identify the importance of particular signaling proteins in shaping the response of a population of beta cells. We simulated a population of 10 000 heterogeneous cells with varying initial protein concentrations responding to PRL stimulation. We used partial least squares regression to analyze the significance and role of each of the varied protein concentrations in producing the response of the cell. Our regression models predict that the concentrations of the cytosolic and nuclear phosphatases strongly influence the response of the cell. The model also predicts that increasing PRL receptor strengthens negative feedback mediated by the inhibitor suppressor of cytokine signaling. These findings reveal biological targets that can potentially be used to modulate the proliferation of pancreatic beta cells to enhance insulin secretion and beta cell regeneration in the context of diabetes.

Funder

USC Provost's Undergraduate Research Fellowship

Publisher

Oxford University Press (OUP)

Subject

Biochemistry,Biophysics

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