Alternative processing of growth hormone receptor transcripts.

G RECEPTOR (GHR) is a transmembrane protein that binds GH with high affinity and specificity. Expression of the receptor is a requirement for cellular responsiveness to GH. The primary transcript that generates the GHR mRNA can undergo alternative processing to produce several related mRNAs, including transcripts that encode the circulating GH-binding protein (GHBP) and a truncated GHR that inhibits normal cellular responses to GH in vitro. In addition, the use of alternative promoters and transcription start sites in the GHR gene-regulatory region generates transcript forms that differ only in the 59-untranslated region (59-UTR). This article will review the transcripts originating from the GHR gene. The introduction will address the expression of GHR and GHBP, the major transcripts of the gene. The second section describes the structure of the GHR gene. The third section describes the types of alternative transcripts produced by the gene, the alternative processing mechanisms that produce them, and the biological functions of their protein products. The final section suggests future studies on the expression and function of alternative GHR transcripts. Normal postnatal growth in mammals requires the presence of GH, a Mr 22,000 polypeptide hormone released primarily from the anterior pituitary gland (reviewed in Ref. 1). GH is bound with high affinity and high specificity by two proteins, the GHR and GHBP. The receptor is associated with the cell membrane of GH target tissues and mediates the somatogenic and metabolic effects of the hormone. The binding protein is found in the serum and forms complexes with circulating GH. Although the exact biological role of the binding protein has not yet been determined, it has been shown to enhance the growth-promoting effects of GH in vivo (2, 3), probably by increasing the half-life of GH in the circulation (4). GHR in most species has a Mr of 100,000–130,000, although smaller and larger molecular weights have been reported (reviewed in Ref. 5). To date, the amino acid sequence of the GHRs from nine species have been published. These species are the human and rabbit (6), mouse (7), rat (8, 9), bovine (10), sheep (11), pig (12), chicken (13), and monkey (14). In all nine species, the amino acid sequence was deduced by sequencing a cDNA clone of the receptor mRNA. Based on the deduced amino acid sequences, GHR is predicted to be a single-pass transmembrane protein approximately 620 amino acids in length; the exact number of amino acids varies slightly from species to species. The receptor is initially synthesized as a preprotein roughly 640 amino acids in length, containing a short signal peptide at its amino terminus for direction of the receptor to the cell surface. The mature receptor (after removal of the signal peptide) has an extracellular hormone-binding domain of approximately 245 amino acids (depending on the species) at its N terminus, a hydrophobic transmembrane domain of 24 amino acids, and an intracellular signaling domain of approximately 350 amino acids at its C terminus. Figure 1 compares the sizes of the mature GHRs from the nine species and lists their percent homology to human GHR. GHBP has been detected in the rabbit (15, 16), human (17, 18), monkey (14, 19), mouse (7, 20), rat (8, 16, 21, 22), goat, dog, cat (19, 23), bovine, horse, pig, sheep, chicken, goose, turkey (24, 25), turtle (26), and guinea pig (27). The reported Mr of the binding protein ranges from 27,500 (24) to 85,000 (18), depending on the species and the method of analysis. GHBP is found in the circulation (reviewed in Ref. 28), intracellularly (29, 30), and associated with cell membranes (31, 32). Under normal physiological conditions, an estimated 40–50% of circulating GH in humans is complexed with the GHBP (33, 34). The exact percentage bound fluctuates diurnally between 10% and 80% due to pulsatile release of GH from the pituitary (35). In nonpregnant mice, estimates of the percent bound GH in serum have ranged from 20% (36) to 50% (37). This percentage increases to more than 90% during pregnancy due to an up-regulation of GHBP relative to GH. Although the substantial amount of GH in serum bound by GHBP, the intracellular presence of GHBP, and cell memAddress reprint requests to: Dr. Frank Talamantes, Department of Biology, Sinsheimer Laboratories, University of California Santa Cruz, Santa Cruz, California 95064 USA. *This work is supported by NIH Grants DK-42361, CA-71590, GM08132, and HD-14966 (to F.T.) 0163-769X/98/$03.00/0 Endocrine Reviews 19(5): 559–582 Copyright © 1998 by The Endocrine Society Printed in U.S.A.