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

C.L. Scott, D. J. Walker, E. Cwiklinski, C. Tait, A. R. Tee, S.C. Land

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    Abstract

    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.

    Original languageEnglish
    Pages (from-to)L455-L471
    Number of pages17
    JournalAmerican Journal of Physiology: Lung Cellular and Molecular Physiology
    Volume299
    Issue number4
    DOIs
    Publication statusPublished - 2010

    Keywords

    • lung development
    • epithelium
    • mesenchyme
    • hypoxia
    • rheb
    • tuberous sclerosis complex
    • HYPOXIA-INDUCIBLE FACTORS
    • EMBRYONIC MOUSE LUNG
    • MAMMALIAN TARGET
    • EPITHELIAL-CELLS
    • GENE-EXPRESSION
    • OXYGEN-TENSION
    • MORPHOGENESIS
    • GROWTH
    • RAPAMYCIN
    • COMPLEX

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