No abstract

Structure of growth-hormone receptor and the class I type of cytokine receptors: common structural features ; cytokine-receptor isoforms ; oligomerization of receptor components initiates cytokine signalling.Role of the Jak kinases in mediating specific functions of growth-hormone receptor and cytokine receptors.Role of signal transducer and activator of transcription (Stat) proteins in growth hormone and cytokine functions.Other pathways activated by cytokine receptors: the mitogen-activated protein kinase pathway; insulin-receptor substrates 1 and 2 and phosphatidylinositol-3-kinase pathways; the Src pathways and other tyrosine kinase pathways; the phospholipase C/protein kinase C/Ca 2ϩ pathways. Regulation of growth-hormone receptor and cytokine receptor signaling: binding sites, internalization and ubiquitination; phosphatases and Janus kinase/Stat inhibitors.Conclusions and future prospects.Keywords : growth-hormone receptor; cytokine receptor; cytokine-receptor isoform ; Janus kinase ; signal transducer and activator of transcription ; signaling; down-regulation; mitogen-activated-protein-kinase pathway.The growth-hormone receptor (GHR) belongs to the class I structural motifs in their extracellular ligand-binding domains and no known catalytic activity such as a tyrosine kinase motif superfamily of cytokine receptors whose transduction processes utilize associated tyrosine kinases of the Janus kinases (Jak) in their cytoplasmic domains. The cytokine receptors can be divided into four different subtypes according to common strucfamily and members of the signal transducers and activators of transcription (Stat). Several reviews [1Ϫ3], including one in this tural features [4]. GHR belongs to the first class of cytokine receptors, also called hematopoietic cytokine receptor family [5, journal [3], have described the structure and the function of these pleiotropic molecules. The aim of this review is therefore 6] (Fig. 1). Type I receptors are characterized by four conserved Cys residues in the amino-terminal part of their extracellular not be to make a compilation of all data reported on activation of Jak and Stat molecules by GHR and cytokine receptors, but domain and the presence of a conserved WSXWS (Trp-Ser-XaaTrp-Ser) motif in the C-terminal part. These repeated Cys are to emphasize how the activation of these molecules is integrated in the specific and regulated functions of growth hormone as also present in the class II (interferon family) and class III (IL-10, tumor necrosis factor family) receptors. Structurally the exwell as few other cytokines. tracellular domain is composed of two fibronectin type III modules [7], each consisting of Ϸ100 amino acids and containing Structure of GHR and the class I type of cytokine receptors seven β-strands that are folded in an anti-parallel fashion so as to form a barrel-like structure. The hinge region between the Common structural features. The cytokine receptors are two barrels structures is where the WSXWS motif was predicted single trans-membrane-domain poly...

The GH receptor (GHR) is a member of the cytokine receptor superfamily; its signaling involves the activation of Janus tyrosine kinases (JAK2) and Stat (signal transducers and activators of transcription) transcription factors. Using truncated and tyrosine mutants of the receptor, we show that different receptor domains are essential for the activation of Stat3 and Stat5. GH-dependent phosphorylation of JAK2, Stat3, and Stat5, as well as transactivation studies with reporter genes containing Stat3 and Stat5 DNA-binding elements, was performed in cells expressing the various GHR mutants. The membrane-proximal region of the receptor necessary for JAK2 activation is sufficient for Stat3 activation. In contrast, C-terminal tyrosine residues of GHR are absolutely required for Stat5 activation. The same residues are also involved in the regulation of JAK2 dephosphorylation, possibly through the activation of a phosphatase. Using in vitro experiments with glutathione-S-transferase fusion proteins, we demonstrate that the SH2 domain of Stat5 binds to the carboxy-terminal tyrosine-phosphorylated residues of GHR. Our results show that a cytokine receptor can mediate differently the activation of distinct Stat proteins that could be involved in cytokine-specific effects.

The cloning of receptor targets procedure, used so far to identify proteins associated with tyrosine kinase receptors was modified to clone SH2 proteins able to bind to the growth hormone receptor (GHR). The cytoplasmic region of GHR, a member of the cytokine receptor superfamily does not contain tyrosine kinase activity. It was thus phosphorylated in bacteria by the Elk tyrosine kinase and radiolabeled to screen a mouse expression library. With this probe, we identified Shc and the p85 subunit of phosphatidylinositol 3-kinase as direct targets of the receptor. The other proteins identified, Csk, Shb, Grb4, and Grb10 are new potential transducers for cytokine receptors. We show in Huh-7 hepatoma cells that Grb10 and GHR associate under GH stimulation. Co-transfections in 293 cells further show that Grb10 interacts with both the GHR and Jak2. Functional tests demonstrate that Grb10 inhibits transcription of two reporter genes containing, respectively, the serum response element of c-fos and the GH response element 2 of the Spi2.1 gene, whereas it has no effect on a reporter gene containing only Stat5 binding elements. Our results suggest that Grb10 is a new target for a member of the cytokine receptor family that down-regulates some GH signaling pathways downstream of Jak2 and independently of Stat5.