Growth hormone receptor signalling pathways.
Reprinted from TRENDS in Endocrinology and Metabolism 12(6), J. Herrington and C. Carter-Su, Signaling pathways activated by the growth hormone receptor, 252-257, 2001, with permission from Elsevier, PMID: 11445442.
Growth hormone (GH) exerts its effect by binding to the extracellular domain of the GH receptor (GHR), where one molecule of GH binds two GHRs. The dimerised GHR then relays its signal by recruiting cytoplasmic tyrosine kinases, which phosphorylate tyrosine residues in the intracellular domain of GHR. Different tyrosine kinases can associate with the GHR, the predominant one being the JAK (Janus kinase) family of proteins, JAK2 in particular. The intracellular domain contains a proline-rich motif, termed ‘box 1’, that is required for the binding and activation of JAK2. The Src family of kinases can also phosphorylate the GHR, and can serve to direct multiple signals through different signalling pathways, thereby initiating different cellular effects.
The phosphotyrosine residues on both the GHR and JAK2 provide docking sites for a variety of signalling proteins that contain phosphotyrosine-binding motifs (such as SH2 domains). The GH-bound receptor induces JAK2 phosphorylation of the various target proteins, leading to different cellular responses. The signalling proteins that bind to GHR-JAK2 often form multi-protein complexes, which contain different enzymes, as well as adaptor molecules that act to mediate protein-protein interactions. Substrates for GHR-JAK2 activation include STATs (signal transducers and activators of transcription), SHCs (Src homology 2a collagen-related), IRSs (insulin receptor substrate), CEBPb (CCAAT/enhancer-binding protein b), CEBPg, CHOP (CEBP homologous protein), GCR (glucocorticoid receptor), EGFR (epidermal growth factor receptor), Elk-1, Grb-10 (adaptor protein), Sap-1a, Csk (carboxy-terminal Src kinase), ATF-2 (activating transcription factor), FAK (focal adhesion kinase), HNF1a (hepatocyte nuclear factor 1a), and HNF-4.
The GHR-JAK2 activation of signalling molecules can result in different cellular responses, some of which involve the activation of transcription from target genes, while others involve metabolic changes. In the examples diagrammed above, GH-induced JAK2 activation of STAT or SHC leads to transcriptional activation, while the activation of IRS results in the induction of the insulin-like action of GH.
GH-stimulated responses can be inhibited through the action of different proteins, which keep GH activity in check in order to prevent unregulated growth. The GHR can be inhibited by SOCS (suppressors of cytokine signalling), which acts by binding to JAK proteins to suppress their kinase activity. Alternatively, GHR can be inhibited by different tyrosine phosphorylases, such as SHP (SH2 domain-containing protein tyrosine phosphatase) proteins, which dephosphorylate both the GHR and JAK2 to suppress signalling.