Abstract:
: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.
journal_name
Endocrinologyjournal_title
Endocrinologyauthors
Jiang J,Wan Y,Wang X,Xu J,Harris JM,Lobie PE,Zhang Y,Zinn KR,Waters MJ,Frank SJdoi
10.1210/en.2011-1336subject
Has Abstractpub_date
2011-12-01 00:00:00pages
4777-88issue
12eissn
0013-7227issn
1945-7170pii
en.2011-1336journal_volume
152pub_type
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