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A Membrane-Fixed, Truncated Isoform of the Human Growth Hormone Receptor¹

Department of Pharmacology (T.A., T.B., M.B.H.Y., Z.H.), Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel; INSERM U468 (F.D., S.A.), Hopital Henri Mondor, 94010 Creteil, France; and Department of Pediatrics (Z.H.), Rambam Medical Center, Haifa, 31096 Israel

Address all correspondence and requests for reprints to: Dr. Ze’ev Hochberg, Faculty of Medicine, Technion, P.O. Box 9649, Haifa 31096, Israel. E-mail: rprzeev{at}tx.technion.ac.il

Previously, we reported the identification of a new human GH receptor (hGHR) messenger RNA species that encodes a smaller hGHR isoform, termed hGHRtr. Its messenger RNA is expressed in several human tissues and predicts a severely truncated GHR protein that lacks 97.5% of the intracellular domain. Because these two hGHR isoforms, which display similar binding affinity, are coexpressed in several tissues, they may reside side by side and, therefore, interrelate. To further characterize the biological properties of hGHRtr in comparison with hGHR, we generated Chinese hamster ovary (CHO) cell lines stably expressing each of these hGHR isoforms. Cross-linking of [¹²⁵I]hGH to CHO/hGHRtr cells revealed a majored specific complex with apparent Mr of 100 kDa, which would indicate the hGHRtr to be in molecular mass form of about 80 kDa. When compared with CHO/hGHR, CHO/hGHRtr cells secreted higher amounts of soluble GH-binding protein (GHBP). In contrast to CHO/hGHR cells, CHO/hGHRtr cells did not exhibit any GH-induced receptor down-regulation, and internalization was markedly reduced. Analysis of the constitutive turnover of cellular hGHR and soluble GHBP showed that incubation of CHO/hGHR cells with cycloheximide caused parallel disappearance of hGHR and GHBP. This contrasted with the stability of GHRtr, which showed no decline after cycloheximide treatment for up to 4 h, suggesting that the bulk GHRtr and GHBP may be derived from preformed proteins. Thus, in contrast to hGHR, hGHRtr is fixed at the cell membrane; it undergoes minimal internalization, no down-regulation by hGH, no constitutive turnover for as long as 4 h, but increased capacity to generate a soluble GHBP. Because hGHRtr failed to undergo ligand-induced internalization, the source of the continuous, undisturbed GHBP released into the medium may be from an intracellular storage pool. The relative abundance of these two hGHR isoforms, through regulation of splicing, could be of critical importance in modulating the biological effects of GH.

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