Abstract
Neurotensin is a peptide hormone released from enteroendocrine cells in the small intestine in response to fat ingestion. Although the mechanisms regulating neurotensin secretion are still incompletely understood, our recent findings implicate a role for extracellular signal–regulated kinase 1 and 2 as positive regulators of free fatty acid-stimulated neurotensin secretion. Previous studies have shown that kinase suppressor of Ras 1 acts as a molecular scaffold of the Raf/MEK/extracellular signal–regulated kinase 1 and 2 kinase cascade and regulates intensity and duration of extracellular signal–regulated kinase 1 and 2 signaling. Here, we demonstrate that inhibition of kinase suppressor of Ras 1 attenuates neurotensin secretion and extracellular signal–regulated kinase 1 and 2 signaling in human endocrine cells. Conversely, we show that overexpression of kinase suppressor of Ras 1 enhances neurotensin secretion and extracellular signal–regulated kinase 1 and 2 signaling. We also show that inhibition of extracellular signal–regulated kinase 2 and exocyst complex component 70, a substrate of extracellular signal–regulated kinase 2 and mediator of secretory vesicle exocytosis, potently inhibits basal and docosahexaenoic acid-stimulated neurotensin secretion, whereas overexpression of exocyst complex component 70 enhances basal and docosahexaenoic acid-stimulated neurotensin secretion. Together, our findings demonstrate a role for kinase suppressor of Ras 1 as a positive regulator of neurotensin secretion from human endocrine cells and indicate that this effect is mediated by the extracellular signal–regulated kinase 1 and 2 signaling pathway. Moreover, we reveal a novel role for exocyst complex component 70 in regulation of neurotensin vesicle exocytosis through its interaction with the extracellular signal–regulated kinase 1 and 2 signaling pathway.
Document Type
Article
Publication Date
3-27-2019
Digital Object Identifier (DOI)
https://doi.org/10.1371/journal.pone.0211134
Funding Information
This work was supported by the National Institutes of Health Grants R01 DK112034 (to B.M.E.), R01 DK048498 (to B.M.E.) and NCI P30 CA177558. S.R. is supported by NIH Training Grant T32 DK007778.
Repository Citation
Rock, Stephanie; Li, Xian; Song, Jun; Townsend, Courtney M.; Weiss, Heidi L.; Rychahou, Piotr G.; Gao, Tianyan; Li, Jing; and Evers, B. Mark, "Kinase Suppressor of Ras 1 and Exo70 Promote Fatty Acid-Stimulated Neurotensin Secretion Through ERK1/2 Signaling" (2019). Markey Cancer Center Faculty Publications. 145.
https://uknowledge.uky.edu/markey_facpub/145
Included in
Cell and Developmental Biology Commons, Endocrinology, Diabetes, and Metabolism Commons, Oncology Commons
Notes/Citation Information
Published in PLOS ONE, v. 14, no. 3, e0211134, p. 1-17.
© 2019 Rock et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.