SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions

Lei L. Chen, Jing Zhu, Jonathan Schumacher, Chongjuan Wei, Latha Ramdas, Victor G. Prieto, Arnie Jimenez, Marco A. Velasco, Sheryl R. Tripp, Robert H.I. Andtbacka, Launce Gouw, George M. Rodgers, Liansheng Zhang, Benjamin K. Chan, Pamela B. Cassidy, Robert S. Benjamin, Sancy A. Leachman, Marsha L. Frazier

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1 Scopus citations

Abstract

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

Original languageEnglish (US)
Article numbere0184154
JournalPloS one
Volume12
Issue number9
DOIs
StatePublished - Sep 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Chen, L. L., Zhu, J., Schumacher, J., Wei, C., Ramdas, L., Prieto, V. G., Jimenez, A., Velasco, M. A., Tripp, S. R., Andtbacka, R. H. I., Gouw, L., Rodgers, G. M., Zhang, L., Chan, B. K., Cassidy, P. B., Benjamin, R. S., Leachman, S. A., & Frazier, M. L. (2017). SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions. PloS one, 12(9), [e0184154]. https://doi.org/10.1371/journal.pone.0184154