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 Cassidy, Robert S. Benjamin, Sancy Leachman, Marsha L. Frazier

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 1 2017

Fingerprint

Endothelin-3
Endothelin B Receptors
endothelins
nitric oxide
Nitric Oxide
secretion
receptors
synthesis
cells
Chemical activation
Nitric Oxide Synthase
Myenteric Plexus
harness
Gastrointestinal Stromal Tumors
extracellular space
Nitric Oxide Synthase Type III
plexus
Endothelial cells
Human Umbilical Vein Endothelial Cells
Extracellular Space

ASJC Scopus subject areas

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

Cite this

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

In: PLoS One, Vol. 12, No. 9, e0184154, 01.09.2017.

Research output: Contribution to journalArticle

Chen, LL, Zhu, J, Schumacher, J, Wei, C, Ramdas, L, Prieto, VG, Jimenez, A, Velasco, MA, Tripp, SR, Andtbacka, RHI, Gouw, L, Rodgers, GM, Zhang, L, Chan, BK, Cassidy, P, Benjamin, RS, Leachman, S & Frazier, ML 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, vol. 12, no. 9, e0184154. https://doi.org/10.1371/journal.pone.0184154
Chen, Lei L. ; Zhu, Jing ; Schumacher, Jonathan ; Wei, Chongjuan ; Ramdas, Latha ; Prieto, Victor G. ; Jimenez, Arnie ; Velasco, Marco A. ; Tripp, Sheryl R. ; Andtbacka, Robert H.I. ; Gouw, Launce ; Rodgers, George M. ; Zhang, Liansheng ; Chan, Benjamin K. ; Cassidy, Pamela ; Benjamin, Robert S. ; Leachman, Sancy ; Frazier, Marsha L. / 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. In: PLoS One. 2017 ; Vol. 12, No. 9.
@article{c9d78647c4be4a2681975c4a8613f3c8,
title = "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",
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.",
author = "Chen, {Lei L.} and Jing Zhu and Jonathan Schumacher and Chongjuan Wei and Latha Ramdas and Prieto, {Victor G.} and Arnie Jimenez and Velasco, {Marco A.} and Tripp, {Sheryl R.} and Andtbacka, {Robert H.I.} and Launce Gouw and Rodgers, {George M.} and Liansheng Zhang and Chan, {Benjamin K.} and Pamela Cassidy and Benjamin, {Robert S.} and Sancy Leachman and Frazier, {Marsha L.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1371/journal.pone.0184154",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - SCF-KIT signaling induces endothelin-3 synthesis and secretion

T2 - Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions

AU - Chen, Lei L.

AU - Zhu, Jing

AU - Schumacher, Jonathan

AU - Wei, Chongjuan

AU - Ramdas, Latha

AU - Prieto, Victor G.

AU - Jimenez, Arnie

AU - Velasco, Marco A.

AU - Tripp, Sheryl R.

AU - Andtbacka, Robert H.I.

AU - Gouw, Launce

AU - Rodgers, George M.

AU - Zhang, Liansheng

AU - Chan, Benjamin K.

AU - Cassidy, Pamela

AU - Benjamin, Robert S.

AU - Leachman, Sancy

AU - Frazier, Marsha L.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85029809655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029809655&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0184154

DO - 10.1371/journal.pone.0184154

M3 - Article

C2 - 28880927

AN - SCOPUS:85029809655

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e0184154

ER -