Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells

Implications for co-ordinated airway and vascular branching in lung development

David J. Walker, Stephen C Land (Lead / Corresponding author)

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Abstract

Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3′ sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10 K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.
Original languageEnglish
Pages (from-to)105-114
Number of pages10
JournalComparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Volume224
Issue numberB
Early online date1 Feb 2018
DOIs
Publication statusPublished - Oct 2018

Fingerprint

Response Elements
Fibroblast Growth Factor 10
Vascular Endothelial Growth Factor A
Blood Vessels
Epithelial Cells
Lung
Rats
Intercellular Signaling Peptides and Proteins
Hypoxia-Inducible Factor 1
Methylation
Histones
Small Interfering RNA
Chemical activation
Growth
Cues
Proteins
Population
Hypoxia

Keywords

  • Lung development
  • Gas exchange
  • Cardio-pulmonary system
  • Hypoxia inducible factor
  • Fibroblast growth factor-10
  • Symmorphosis
  • Epithelial Cells/metabolism
  • Vascular Endothelial Growth Factor A/genetics
  • Fibroblast Growth Factor 10/genetics
  • Humans
  • Membrane Proteins/genetics
  • Lung/blood supply
  • Rats
  • Fetus/blood supply
  • Rats, Sprague-Dawley
  • Signal Transduction/physiology
  • Animals
  • Intracellular Signaling Peptides and Proteins/genetics
  • Nerve Tissue Proteins/genetics

Cite this

@article{e281f223d0c5482c80f20ad0f45c397c,
title = "Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells: Implications for co-ordinated airway and vascular branching in lung development",
abstract = "Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3′ sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10 K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.",
keywords = "Lung development, Gas exchange, Cardio-pulmonary system, Hypoxia inducible factor, Fibroblast growth factor-10, Symmorphosis, Epithelial Cells/metabolism, Vascular Endothelial Growth Factor A/genetics, Fibroblast Growth Factor 10/genetics, Humans, Membrane Proteins/genetics, Lung/blood supply, Rats, Fetus/blood supply, Rats, Sprague-Dawley, Signal Transduction/physiology, Animals, Intracellular Signaling Peptides and Proteins/genetics, Nerve Tissue Proteins/genetics",
author = "Walker, {David J.} and Land, {Stephen C}",
note = "We are grateful to Dr. Will Fuller (Dundee) for generous gift of reagents and advice on Spry2 palmitoylation, Dr. S Rocha (Dundee) for ChIP advice and Dr. R. Nookala for advice on Spry2-DNA recognition sequences. This work was supported by a Wellcome Trust project grant 088032/Z/08/Z to SCL.",
year = "2018",
month = "10",
doi = "10.1016/j.cbpb.2018.01.007",
language = "English",
volume = "224",
pages = "105--114",
journal = "Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology",
issn = "1096-4959",
publisher = "Elsevier",
number = "B",

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TY - JOUR

T1 - Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells

T2 - Implications for co-ordinated airway and vascular branching in lung development

AU - Walker, David J.

AU - Land, Stephen C

N1 - We are grateful to Dr. Will Fuller (Dundee) for generous gift of reagents and advice on Spry2 palmitoylation, Dr. S Rocha (Dundee) for ChIP advice and Dr. R. Nookala for advice on Spry2-DNA recognition sequences. This work was supported by a Wellcome Trust project grant 088032/Z/08/Z to SCL.

PY - 2018/10

Y1 - 2018/10

N2 - Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3′ sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10 K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.

AB - Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3′ sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10 K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.

KW - Lung development

KW - Gas exchange

KW - Cardio-pulmonary system

KW - Hypoxia inducible factor

KW - Fibroblast growth factor-10

KW - Symmorphosis

KW - Epithelial Cells/metabolism

KW - Vascular Endothelial Growth Factor A/genetics

KW - Fibroblast Growth Factor 10/genetics

KW - Humans

KW - Membrane Proteins/genetics

KW - Lung/blood supply

KW - Rats

KW - Fetus/blood supply

KW - Rats, Sprague-Dawley

KW - Signal Transduction/physiology

KW - Animals

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Nerve Tissue Proteins/genetics

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U2 - 10.1016/j.cbpb.2018.01.007

DO - 10.1016/j.cbpb.2018.01.007

M3 - Article

VL - 224

SP - 105

EP - 114

JO - Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology

JF - Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology

SN - 1096-4959

IS - B

ER -