The growth hormone receptor

GH induces its characteristic biological effects by binding to a specific cell surface receptor. The human receptor is a single-chain 620 amino acid transmembrane polypeptide. Sequence analysis 

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Dimerization of the growth hormone receptor is a sequential process... 

The prolactin receptor, PER, which regulates milk production in mammals, belongs to the same receptor class as the growth hormone receptor. In addition to binding the hormone prolactin, PER also binds and is activated by growth hormone. The extracellular domain of PER forms a very stable 1 1 complex with growth hormone in solution this complex has been crystallized and its structure determined (Figure 13.21). We shall compare this structure with the 1 2 complex of the same hormone with GHR. 

Figure 13.22 Hormone-receptor interactions involving the domain-domain linker region in the receptor, (a) Interactions between the growth hormone (red) and the growth hormone receptor (blue) linker region. Glu 127 of the receptor forms a salt bridge to Arg 167 in the hormone, (b) The same interaction area in the growth hormone (red)-prolactin receptor (green) complex. The displacement of the linker region due to differences in the domain orientations have brought Asp 124 in the prolactin receptor into contact with Arg 167 of the hormone. (Adapted from W. Somers et al.. Nature 372 478-481, 1994.)...

Pearce, K.H., Jr., M.H. Ultsch, R.F. Kelley, A.M. de Vos, and J.A. Wells. 1996. Structural and mutational analysis of affinity-inert contact residues at the growth hormone-receptor interface. Biochemistry 35 10300-10307. 

Covers, R., T. ten Broeke, P. van Kerkhof, A. L. Schwartz, and G. J. Strous. Identification of a novel ubiquitin conjugation motif required for ligand-induced internalization of the growth hormone receptor. Embo J. 18 28-36.1999. 

Although ubiquitin-conjugation of receptors in mammalian cells has been observed, the function of this modification seems less clear. In the case of the growth hormone receptor (GH-receptor) and the epithelial Na-t- channel (ENaC), it seems likely that ubiquitin-conjugation triggers their endocytosis. 

Wells, J. A (1995) Structural and functional epitopes in the growth hormone receptor complex. Biotechnology 13,647-651. 

Wells JA (1996) Binding in the growth hormone receptor complex, Proc Natl Acad Sci USA, 93 1-6... 

Dimerization is not restricted to receptors. It is a property of many regulatory proteins and enzymes. Homo- and heterodimerization occur in many signal transmitters and transcriptional activators, as we shall see later. Out of many examples of receptor dimerization, I have selected the growth hormone receptor and closely related receptors, because X-ray crystaUographers have provided detailed information on the structural basis of ligand-induced oligomerization. 

Some ligands induce dimerization of the receptors to which they bind. Such a receptor contains an extracellular domain that binds the ligand, a transmembrane region, and a cytosolic domain that either binds or contains a protein kinase. The growth-hormone receptor participates in an example of this type of signal-transduction pathway. Dimerization of the receptor activates Janus kinase 2, a protein kinase associated with the intracellular part of the receptor. The kinase, in turn, phosphorylates and activates a transcription factor called STAT5. 

The mutated hormone would bind to the growth-hormone receptor but would not favor receptor dimerization. Thus, it would not stimulate the JAK-STAT signaling pathway. Such a mutated hormone might be useful as a competitive inhibitor for growth hormone. It would block the activity of native growth hormone. 

Trainer PJ, Drake WM, Katznelson L, et al. Treatment of acromegaly with the growth hormone-receptor antagonist Pegvisomant. N Engl J Med 2000 342 1171-1177. 

JAK2 Janus kinase 2 an enzyme that will phosphorylate tyrosine residues on target proteins. JAK2 is bound to the growth hormone receptor but is inactive until the receptor binds the hormone. When hormone binds the receptor, it triggers dimerization and activates JAK2. 

For some cytokine receptors, including the growth hormone receptor and several interleukin receptors, soluble isoforms have been described that comprise all or part of the extracellular domain and may be able to bind the extracellular ligands. By association with other subunits of heterooligomeric receptors, e. g., the gpl30 subunit, these soluble isoforms can function as agonists or antagonists. 

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