Date Published: March 27, 2019
Publisher: Public Library of Science
Author(s): Stephanie Rock, Xian Li, Jun Song, Courtney M. Townsend, Heidi L. Weiss, Piotr Rychahou, Tianyan Gao, Jing Li, B. Mark Evers, Jong-In Park.
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.
Obesity in the United States has reached epidemic levels, with approximately 70% of the population overweight and over 30% of overweight individuals classified as obese [1, 2]. Cancers associated with overweight and obesity account for approximately 40% of all diagnosed cancers in the United States . Excess adiposity is thought to contribute to the development of cancer through the release of free fatty acids (FFAs) by adipose tissue, which have been shown to promote tumorigenesis by serving as metabolic fuel for highly proliferating cells [3–6]. FFAs have also been demonstrated to regulate expression and secretion of hormones and neuropeptides, including the gastrointestinal neuropeptide neurotensin (NT), which is implicated in the promotion of obesity and the development of several types of cancer [7–12].
FAs and NT play stimulatory and intersecting roles in the development of obesity and cancer. Our group recently demonstrated that stimulation of NT secretion by the unsaturated FA, DHA, is mediated by ERK1/2 signaling [11, 54]. Here, we examine the role of KSR1 on DHA-stimulated NT secretion. We show that KSR1 promotes DHA-stimulated NT secretion through the ERK1/2 signaling pathway. We also show that Exo70 inhibition reduces, while its overexpression enhances NT secretion and ERK1/2 phosphorylation. Collectively, the data presented in our current study implicate KSR1 and Exo70 as positive regulators of NT secretion that are integrated through the ERK1/2 signaling pathway.