Jing Jiang’s paper entitled “Inhibitory GH receptor extracellular domain monoclonal antibodies: three dimensional epitope mapping” was featured on the cover of Endocrinology‘s December 2011 issue. This paper has been selected as the Department of Medicine’s February 2012 Paper of the Month.
Jing Jaing Jing Jiang, M.S.Division of Endocrinology
BDB 762
(205) 934-9856
jjiang@uab.edu
Endocrinology. 2011 Dec;152(12):4777-88. Epub 2011 Oct 11.
Inhibitory GH receptor extracellular domain monoclonal antibodies: three dimensional epitope mapping
Jiang J, Wan Y, Wang X, Xu J, Harris JM, Lobie PE, Zhang Y, Zinn KR, Waters MJ, Frank SJ.
Abstract:
Endocrinology-cover-picture GH receptor (GHR) mediates the anabolic and metabolic effects of GH. We previously characterized a monoclonal antibody (anti-GHR(ext-mAb)) that reacts with subdomain 2 of the rabbit GHR extracellular domain (ECD) and is a conformation-specific inhibitor of GH signaling in cells bearing rabbit or human GHR. Notably, this antibody has little effect on GH binding and also inhibits inducible metalloproteolysis of the GHR that occurs in the perimembranous ECD stem region. In the current study, we demonstrate that anti-GHR(ext-mAb) inhibits GH-dependent cellular proliferation and also inhibits hepatic GH signaling in vivo in mice that adenovirally express rabbit GHR, as assessed with our noninvasive bioluminescence hepatic signaling assay. A separate monoclonal antibody (anti-GHR(mAb 18.24)) is a sister clone of anti-GHR(ext-mAb). Here, we demonstrate that anti-GHR(mAb 18.24) also inhibits rabbit and human GHR signaling and inducible receptor proteolysis. Further, we use a random PCR-generated mutagenic expression system to map the three-dimensional epitopes in the rabbit GHR ECD for both anti-GHR(ext-mAb) and anti-GHR(mAb 18.24). We find that each of the two antibodies has similar, but nonidentical, discontinuous epitopes that include regions of subdomain 2 encompassing the dimerization interface. These results have fundamental implications for understanding the role of the dimerization interface and subdomain 2 in GHR activation and regulated GHR metalloproteolysis and may inform development of therapeutics that target GHR.
Biographical Sketch
Ms. Jing Jiang received the M.S. in Molecular Biology from Southern Connecticut State University and worked as a Research Associate at Yale University prior to coming to UAB in 1994. Ms. Jiang has served as Laboratory Manager since that time in Dr. Stuart Frank’s laboratory in the Division of Endocrinology, Diabetes, and Metabolism. She is involved in various studies pertaining to growth hormone signaling and GH receptor structure/function relationships
Research Interests
The Frank lab is interested in various aspects of growth hormone and prolactin action and how they are modulated under physiological and pathological conditions. Specifically, ongoing research projects are directed at: better understanding structure/function relationships and signaling mechanisms of both the growth hormone and prolactin receptors and how those two receptors physically and functionally interact; novel interactions between the growth hormone and IGF-1 receptors and how such interactions influence growth hormone actions in bone and cancer cells; the development of monoclonal antibody antagonists of growth hormone action as potential therapeutics; regulated metalloproteolytic processing of the growth hormone receptor and how this influences growth hormone sensitivity in liver and other target organs in the setting of sepsis; and circadian regulation of growth hormone receptor abundance and growth hormone sensitivity in vivo.
