Growth Hormone Signaling

Growth Hormone(GH) and Insulin-Like Growth Factor-1(IGF-1) are two important anabolic hormones that regulate metabolic processes including protein synthesis in almost all tissues throughout the lifespan of mammals. GH is required for normal postnatal growth, having a critical role in bone growth as well as important regulatory effects on protein, carbohydrate and lipid metabolism. The physiological effects of GH are brought about by the Growth hormone receptor (GHR).Biologically active GH binds to two of its transmembrane receptors: GHRs, causes dimerization of GHR, activation of the GHR-associated JAK2, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAPKs, IRS1, PI3K, DAG, PKC, and STATs. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism. Cross-talk among these signaling cascades in regulating specific genes suggests a GH-regulated signaling network. Activation of PI3K and IRS1 by GH signaling results in increased glucose uptake by effecting the translocation of GLUT4 from an intracellular compartment to the plasma membrane. PI3K also activates the Akt/PKB Pathway through PDK-1 that culminates in cell survival. STAT proteins 1, 3, and 5 are recruited to the GHR-JAK2 complex and become tyrosine phosphorylated. The STAT proteins play an important role in the regulation of gene expression by GH.GH regulates two transcription factors associated with the c-fos Serum Response Element , Serum Response Factor and Elk1 or another Ternary Complex Factor (TCF), which contribute to GH-dependent gene expression. GHRE in the Spi 2.1 promoter contains two GAS sites that are recognized by STAT5. In addition, γ-Activated Sequence-Like Elements (GLE) present in genes such as Spi 2.1, β casein, and CYP 3A10/6-β-hydroxylase are also recognized and regulated by STAT5. Binding of STAT1 and STAT3 to the Sis-Inducible Element (SIE) in response to GH contribute to the regulation of c-Fos gene expression. STAT5 also participates in c-Fos gene expression in a SIE dependent manner. GH-induced association of the GHR-JAK2 complex leads to activation of the Ras-MAPK pathway. Activated MAPKs ERK1 and ERK2 phosphorylate a TCF, which leads to transcriptional activation via the SRE. GH may also regulate the phosphorylation of SRF via p90 Ribosomal S6 Kinase (p90RSK). GH has also been reported to stimulate the synthesis and binding of the transcription factors CEBP-β and CEBP-δ, which have been implicated in cell differentiation and proliferation. GH-dependent MAPK activation plays a role in the regulation of nuclear relocalization of C/EBP-β. The actions of human GH are also achieved through the stimulation of IGF production in target tissues. GHR dimerization activates the synthesis and secretion of IGF1.Factors like SOCS and SHP1 play an important role in the down regulation of signaling by GH. During a GH response, SHP1 translocates to the nucleus and associates with phosphorylated STAT5, suggesting that it can participate in the dephosphorylation of nuclear STAT5. At the same time, SHP1 is also associated with JAK2 and appears to be involved in the attenuation of GH-activated JAK activity.GH is an anabolic hormone that induces positive nitrogen balance in intact animals and protein synthesis in muscle. GH is regulated by nutrition and by the hormonal and genetic milieu that controls the timing and rate of growth.