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.
Highlights
Nitric oxide (NO) is produced by three isoforms of NO synthase (NOS), neuronal NOS, endothelial NOS, and inducible NOS. endothelial nitric oxide synthase (eNOS) and nNOS are expressed mainly in endothelial cells and neurons respectively and their activation is Ca2+-dependent
Unlike eNOS and nNOS, activation of inducible nitric oxide synthase (iNOS) does not depend on Ca2+, and is mainly induced by inflammation. iNOS activation typically generates a burst of excessive NO production, triggers apoptosis, induces cell death, and has been associated with degenerative diseases [3]
Dominant activating-mutations of either KIT or platelet-derived growth factor receptor (PDGFR)-A can lead to gastrointestinal stromal tumor (GIST)
Summary
Nitric oxide (NO) is produced by three isoforms of NO synthase (NOS), neuronal NOS (nNOS, type 1), endothelial NOS (eNOS, type 3), and inducible NOS (iNOS, type 2). eNOS and nNOS are expressed mainly in endothelial cells and neurons respectively and their activation is Ca2+-dependent. ENOS and nNOS are expressed mainly in endothelial cells and neurons respectively and their activation is Ca2+-dependent. The constitutive low level of NO generated by eNOS and or nNOS mediates diverse cell-specific physiological functions [1,2]. Unlike eNOS and nNOS, activation of iNOS does not depend on Ca2+, and is mainly induced by inflammation. INOS activation typically generates a burst of excessive NO production, triggers apoptosis, induces cell death, and has been associated with degenerative diseases [3]. The diverse physiological role of NO depends on target cell types, downstream signaling effector molecules, micro environmental cues (presence or absence of growth factors or cytokines), the source of NO generation (by eNOS, or nNOS, or iNOS), constitutive vs burst NO production, and concentration (nanomolar vs micromolar NO levels). Timely delivery of precise amount of NO generated by the specific NOS activation is critical for cell-specific functions, maintaining homeostasis, and survival
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