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Sulfated glycans engage the Ang–Tie pathway to regulate vascular development

Griffin, Matthew E. and Sorum, Alexander W. and Miller, Gregory M. and Goddard, William A., III and Hsieh-Wilson, Linda C. (2020) Sulfated glycans engage the Ang–Tie pathway to regulate vascular development. Nature Chemical Biology . ISSN 1552-4450. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20200728-132413236

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Abstract

The angiopoietin (Ang)–Tie pathway is essential for the proper maturation and remodeling of the vasculature. Despite its importance in disease, the mechanisms that control signal transduction through this pathway are poorly understood. Here, we demonstrate that heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang–Tie signaling through direct interactions with both Ang ligands and Tie1 receptors. HS GAGs formed ternary complexes with Ang1 or Ang4 and Tie2 receptors, resulting in potentiation of endothelial survival signaling. In addition, HS GAGs served as ligands for the orphan receptor Tie1. The HS–Tie1 interaction promoted Tie1–Tie2 heterodimerization and enhanced Tie1 stability within the mature vasculature. Loss of HS–Tie1 binding using CRISPR–Cas9-mediated mutagenesis in vivo led to decreased Tie protein levels, pathway suppression and aberrant retinal vascularization. Together, these results reveal that sulfated glycans use dual mechanisms to regulate Ang–Tie signaling and are important for the development and maintenance of the vasculature.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41589-020-00657-7DOIArticle
https://rdcu.be/b76KLPublisherFree ReadCube access
ORCID:
AuthorORCID
Griffin, Matthew E.0000-0001-9549-4418
Sorum, Alexander W.0000-0003-2526-1445
Miller, Gregory M.0000-0002-7595-7996
Goddard, William A., III0000-0003-0097-5716
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Alternate Title:Sulfated glycans engage the Ang/Tie pathway to regulate postnatal vascular development
Additional Information:© 2020 Springer Nature Limited. Received 15 August 2019; Accepted 20 August 2020; Published 05 October 2020. We thank S. Pease and staff of the Caltech Genetically Engineered Mouse Services Core for help with generating the Tie1-2A mouse line and J. Costanza and A. Gomez of the Caltech Office of Laboratory Animal Resources for mouse line care and maintenance. We also thank J. Vielmetter and the Caltech Protein Expression Center of the Beckman Institute for help with conducting the SPR experiments. This work was supported by the NIH (5R01GM093627 and 5R01GM127920 to L.C.H.-W.) and the National Science Foundation (CBET-1805022 to W.A.G., DGE-1144469 to M.E.G. and DGE-1745301 to A.W.S.). Data availability: Data generated or analyzed during this study are included in the article and related Supplementary Information or are available from the corresponding author on reasonable request. Publicly available data used in this study include the Tie2 crystal structure (PDB 2GY5), the Tie1 protein sequence (UniProt P35590), the Dec. 2011 murine genome assembly (GRCm38/mm10) and the CHOPCHOP gRNA design tool (https://chopchop.cbu.uib.no/). Source data are provided with this paper. Author Contributions: M.E.G. and L.C.H.-W. conceived the project. Unless otherwise noted, M.E.G. performed the experimental work. A.W.S. conducted some of the microarray, ELISA and cell imaging assays. G.M.M. aided in assay optimization for initial binding experiments and conducted all computational work under the guidance of W.A.G.III. All authors contributed to the design of the experimental and computational work and to data analysis, discussed the results and commented on the manuscript. M.E.G. and L.C.H.-W. wrote the manuscript. L.C.H.-W. supervised the project. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIH5R01GM093627
NIH5R01GM127920
NSFCBET-1805022
NSF Graduate Research FellowshipDGE-1144469
NSF Graduate Research FellowshipDGE-1745301
Subject Keywords:Carbohydrates; Cardiovascular biology; Cell signalling; Glycobiology
Record Number:CaltechAUTHORS:20200728-132413236
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200728-132413236
Official Citation:Griffin, M.E., Sorum, A.W., Miller, G.M. et al. Sulfated glycans engage the Ang–Tie pathway to regulate vascular development. Nat Chem Biol (2020). https://doi.org/10.1038/s41589-020-00657-7
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104609
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:05 Oct 2020 21:16
Last Modified:05 Oct 2020 21:50

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