No evidence of Gremlin1-mediated activation of VEGFR2 signaling in endothelial cells

Dutton, L. R. , O'Neill, C. L., Medina, R. J. and Brazil, D. P. (2019) No evidence of Gremlin1-mediated activation of VEGFR2 signaling in endothelial cells. Journal of Biological Chemistry, 294(48), pp. 18041-18045. (doi: 10.1074/jbc.AC119.010148) (PMID:31604823) (PMCID:PMC6885617)

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Canonical Gremlin1 (GREM1) signaling involves binding to and sequestering bone morphogenetic proteins (BMPs) in the extracellular matrix, preventing the activation of cognate BMP receptor. Exquisite temporospatial control of the GREM1-BMP interaction is required during development, and perturbation of this balance leads to abnormal limb formation and defective kidney development. In addition to inhibition of BMP signaling, several other noncanonical signaling modalities of GREM1 have been postulated. Some literature reports have suggested that GREM1 can bind to and activate vascular endothelial growth factor receptor-2 (VEGFR2) in endothelial cells, human kidney epithelial cells, and others. These reports suggest that the GREM1 → VEGFR2 signaling can drive angiogenesis both in vitro and in vivo. We report here that, despite exhaustive attempts, we did not observe GREM1 activation of VEGFR2 in any of the cell lines reported by the above-mentioned studies. Incubation of endothelial colony–forming cells (ECFCs) or human umbilical vein endothelial cells (HUVECs) with recombinant VEGF triggered a robust increase in VEGFR2 tyrosine phosphorylation. In contrast, no VEGFR2 phosphorylation was detected when cells were incubated with recombinant GREM1 over a range of time points and concentrations. We also show that GREM1 does not interfere with VEGF-mediated VEGFR2 activation, suggesting that GREM1 does not bind with any great affinity to VEGFR2. Measurements of ECFC barrier integrity revealed that VEGF induces barrier function disruption, but recombinant human GREM1 had no effect in this assay. We believe that these results provide an important clarification of the potential interaction between GREM1 and VEGFR2 in mammalian cells.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Dutton, Ms Louise
Authors: Dutton, L. R., O'Neill, C. L., Medina, R. J., and Brazil, D. P.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:11 October 2019
Copyright Holders:Copyright © 2019 Dutton et al.
First Published:First published in Journal of Biological Chemistry 294(48): 18041-18045
Publisher Policy:Reproduced under a Creative Commons License

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