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Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis

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Abstract

Secreted frizzled-related protein 2 (SFRP2) is a pro-angiogenic factor expressed in the vasculature of a wide variety of human tumors, and modulates angiogenesis via the calcineurin-dependent nuclear factor of activated T-cells cytoplasmic 3 (NFATc3) pathway in endothelial cells. However, until now, SFRP2 receptor for this pathway was unknown. In the present study, we first used amino acid alignments and molecular modeling to demonstrate that SFRP2 interaction with frizzled-5 (FZD5) is typical of Wnt/FZD family members. To confirm this interaction, we performed co-immunofluorescence, co-immunoprecipitation, and ELISA binding assays, which demonstrated SFRP2/FZD5 binding. Functional knock-down studies further revealed that FZD5 is necessary for SFRP2-induced tube formation and intracellular calcium flux in endothelial cells. Using protein analysis on endothelial cell nuclear extracts, we also discovered that FZD5 is required for SFRP2-induced activation of NFATc3. Our novel findings reveal that FZD5 is a receptor for SFRP2 and mediates SFRP2-induced angiogenesis via calcineurin/NFATc3 pathway in endothelial cells.

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Acknowledgements

We thank the Protein Expression and Purification Core Lab at University of North Carolina at Chapel Hill for production of human SFRP2 recombinant protein. This work was supported by National Institute of Health (1R01CA142657-A1 and 1U01CA189281-01A1 to NK-D), and the Kristin Ann Carr Foundation. Microscopy was supported in part by the Cell and Molecular Imaging Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313). Supported in part by the Biostatistics Shared Resource, Hollings Cancer Center, MUSC (P30 CA138313).

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Authors and Affiliations

  1. Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, USA

    Yuri K. Peterson

  2. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA

    Patrick Nasarre, Ingrid V. Bonilla, Eleanor Hilliard & Nancy Klauber-DeMore

  3. Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Jennifer Samples

  4. Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA

    Thomas A. Morinelli

  5. Department of Public Health Science, Medical University of South Carolina, Charleston, SC, 29425, USA

    Elizabeth G. Hill

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  1. Yuri K. Peterson
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Correspondence to Nancy Klauber-DeMore.

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Peterson, Y.K., Nasarre, P., Bonilla, I.V. et al. Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis. Angiogenesis 20, 615–628 (2017). https://doi.org/10.1007/s10456-017-9574-5

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