High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta

Authors

Emmanuel Boateng, The Ohio State University College of Medicine, Columbus, OH, United States of America.
Joanne T. deKay, Johns Hopkins University, Baltimore, MD, United States of America.
Sarah M. Peterson, Maine Medical Center Research Institute, Scarborough, ME, United States of America; IDEXX Laboratories, Westbrook, ME, United States of America.
Jacob Boles, Maine Medical Center Research Institute, Scarborough, ME, United States of America.
Nathan Pinnette, University of Rochester, Rochester, NY, United States of America.
Mary W. Sorcher, Department of Biology, University of Southern Maine, Portland, ME, United States of America; Department of Biology, University of Nevada, Reno, NV, United States of America.
Michael P. Robich, Maine Medical Center Research Institute, Scarborough, ME, United States of America; Maine Medical Center, Cardiovascular Institute, Portland, ME, United States of America.
Douglas B. Sawyer, Maine Medical Center Research Institute, Scarborough, ME, United States of America; Maine Medical Center, Cardiovascular Institute, Portland, ME, United States of America.
Sergey Ryzhov, Maine Medical Center Research Institute, Scarborough, ME, United States of America. Electronic address: sryzhov@mmc.org.

Document Type

Article

Publication Date

6-15-2020

Institution/Department

MaineHealth Institute for Research

Journal Title

Life sciences

MeSH Headings

Adult; Aged; Antibodies, Neutralizing (immunology); Cell Survival (physiology); Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Neuregulin-1 (metabolism); Phosphorylation; Receptor, ErbB-3 (metabolism)

Abstract

Neuregulin-1β (NRG-1) is a membrane-bound or secreted growth and differentiation factor that mediates its action by binding to ErbB receptors. Circulating levels of NRG-1 are characterized by large inter-individual variability with the range of absolute values covering two orders of magnitude, from hundreds to tens of thousands of picograms per milliliter of blood. NRG-1 signaling via ErbB receptors contributes to the cell survival and downregulation of the inflammatory response. A higher level of circulating NRG-1 may indicate increased shedding of membrane-bound NRG-1, which in turn can contribute to better protection against cardiovascular stress or injury. However, it is unknown whether circulating NRG-1 can induce activation of ErbB receptors. In the current study, we performed an analysis of circulating NRG-1 functional activity using a cell-based ELISA measuring phosphorylation of ErbB3 induced by blood plasma obtained from healthy donors. We found high levels of ErbB3 activating activity in human plasma. No correlations were found between the levels of circulating NRG-1 and plasma ErbB3 activating activity. To determine the direct effect of circulating NRG-1, we incubated plasma with neutralizing antibody, which prevented the stimulatory effect of recombinant NRG-1 on activation of ErbB3. No effect of the neutralizing antibody was found on plasma-induced phosphorylation of ErbB3. We also found that a significant portion of circulating NRG-1 is comprised of full-length NRG-1 associated with large extracellular vesicles. Our results demonstrate that circulating NRG-1 does not contribute to plasma-induced ErbB3 activating activity and emphasizes the importance of functional testing of NRG-1 proteins in biological samples.

First Page

117634

Recommended Citation

Boateng E, deKay JT, Peterson SM, et al. High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta. Life Sci. 2020;251:117634. doi:10.1016/j.lfs.2020.117634