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Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock

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Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. / Scott, C.L.; Walker, D. J.; Cwiklinski, E.; Tait, C.; Tee, A. R.; Land, S.C.

In: American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol. 299, No. 4, 2010, p. L455-L471.

Research output: Contribution to journalArticle

Harvard

Scott, CL, Walker, DJ, Cwiklinski, E, Tait, C, Tee, AR & Land, SC 2010, 'Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock' American Journal of Physiology: Lung Cellular and Molecular Physiology, vol 299, no. 4, pp. L455-L471.

APA

Scott, C. L., Walker, D. J., Cwiklinski, E., Tait, C., Tee, A. R., & Land, S. C. (2010). Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. American Journal of Physiology: Lung Cellular and Molecular Physiology, 299(4), L455-L471doi: 10.1152/ajplung.00348.2009

Vancouver

Scott CL, Walker DJ, Cwiklinski E, Tait C, Tee AR, Land SC. Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2010;299(4):L455-L471.

Author

Scott, C.L.; Walker, D. J.; Cwiklinski, E.; Tait, C.; Tee, A. R.; Land, S.C. / Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock.

In: American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol. 299, No. 4, 2010, p. L455-L471.

Research output: Contribution to journalArticle

Bibtex - Download

@article{e68c19cf831b4d1685d30cd42547c30f,
title = "Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock",
author = "C.L. Scott and Walker, {D. J.} and E. Cwiklinski and C. Tait and Tee, {A. R.} and S.C. Land",
year = "2010",
volume = "299",
number = "4",
pages = "L455--L471",
journal = "American Journal of Physiology: Lung Cellular and Molecular Physiology",
issn = "1040-0605",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock

A1 - Scott,C.L.

A1 - Walker,D. J.

A1 - Cwiklinski,E.

A1 - Tait,C.

A1 - Tee,A. R.

A1 - Land,S.C.

AU - Scott,C.L.

AU - Walker,D. J.

AU - Cwiklinski,E.

AU - Tait,C.

AU - Tee,A. R.

AU - Land,S.C.

PY - 2010

Y1 - 2010

N2 - <p>Scott CL, Walker DJ, Cwiklinski E, Tait C, Tee AR, Land SC. Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. Am J Physiol Lung Cell Mol Physiol 299: L455-L471, 2010. First published July 9, 2010; doi:10.1152/ajplung.00348.2009.-Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1 alpha (HIF-1 alpha) vasculogenic activity through an NH2-terminal mTOR binding (TOS) motif. We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10/FGF-receptor2b/Spry2 regulator of airway branching. First, we tested if the HIF-1 alpha TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1 alpha activity at fetal PO2 (23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1 alpha by mTORC1 was abolished on expression of a HIF-1 alpha (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10/FGFR2b/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1(-/-) knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal PO2, FGF-10 induced mTORC1 and amplified HIF-1 alpha activity and VEGF secretion without induction of ERK1/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1 alpha-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator.</p>

AB - <p>Scott CL, Walker DJ, Cwiklinski E, Tait C, Tee AR, Land SC. Control of HIF-1 alpha and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. Am J Physiol Lung Cell Mol Physiol 299: L455-L471, 2010. First published July 9, 2010; doi:10.1152/ajplung.00348.2009.-Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1 alpha (HIF-1 alpha) vasculogenic activity through an NH2-terminal mTOR binding (TOS) motif. We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10/FGF-receptor2b/Spry2 regulator of airway branching. First, we tested if the HIF-1 alpha TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1 alpha activity at fetal PO2 (23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1 alpha by mTORC1 was abolished on expression of a HIF-1 alpha (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10/FGFR2b/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1(-/-) knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal PO2, FGF-10 induced mTORC1 and amplified HIF-1 alpha activity and VEGF secretion without induction of ERK1/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1 alpha-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator.</p>

KW - lung development

KW - epithelium

KW - mesenchyme

KW - hypoxia

KW - rheb

KW - tuberous sclerosis complex

KW - HYPOXIA-INDUCIBLE FACTORS

KW - EMBRYONIC MOUSE LUNG

KW - MAMMALIAN TARGET

KW - EPITHELIAL-CELLS

KW - GENE-EXPRESSION

KW - OXYGEN-TENSION

KW - MORPHOGENESIS

KW - GROWTH

KW - RAPAMYCIN

KW - COMPLEX

U2 - 10.1152/ajplung.00348.2009

DO - 10.1152/ajplung.00348.2009

M1 - Article

JO - American Journal of Physiology: Lung Cellular and Molecular Physiology

JF - American Journal of Physiology: Lung Cellular and Molecular Physiology

SN - 1040-0605

IS - 4

VL - 299

SP - L455-L471

ER -

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