Growth hormone receptor (GHR) signaling (WP2891)

Signal transducers and activators transcription (STAT) proteins are cytoplasmic transcription factors containing SH2 domains that bind to the activated GHR and become phosphorylated by JAK2. activation of the GH receptor can also initiate signal transduction via the Ras/Raf/mitogen-activated protein (MAP) kinase pathway leading to effects on gene transcription and metabolism.GH also stimulates phosphorylation of the insulin receptor substrates 1,2,3(IRS-1,2,3,4)with subsequent activation of the phosphoinositol-3-kinase (PI3K) resulting in stimulation of glucose transport. This pathway was based on the below review articles.
Initiation of GH signaling requires that a single GH molecule binds to two GHR monomers causing receptor dimerization. Proper dimerization occurs by sequential binding of the receptor to a high affinity site in GH followed by recruitment of the second receptor to a low affinity site (Cunningham, Ultsch et al. 1991). However, some evidence suggest the existence of preformed, unliganded receptor dimers that are activated by a ligand-induced change in receptor conformation (Behncken and Waters 1999; Frank 2002). In accordance with the receptor dimerization mechanism, dose- response experiments give rise to biphasic, bell-shaped kinetics (Ilondo, Damholt et al. 1994). GHR dimerization and ligand-induced conformational change bring the intracellular receptor domains into close proximity whereby downstream signaling events are triggered. Receptor-associated tyrosine kinase JAK2 (Janus kinase 2) is activated (Argetsinger, Campbell et al. 1993) and phosphorylates cytoplasmic domains of GHRs on tyrosine residues, thereby creating docking sites for SH2 (src homology 2) containing proteins (Herrington and Carter-Su 2001). Signal transducers and activators of transcription (STAT) proteins are cytoplasmic transcription factors containing SH2 domains that bind to the activated GHR and become phosphorylated by JAK2. Phosphorylated members of the STAT family homo- or heterodimerize and translocate to the nucleus where they bind to specific DNA target elements and activate gene transcription (Herrington, Smit et al. 2000). Activation of the GH receptor can also initiate signal transduction via the Ras/Raf/mitogen-activated protein (MAP) kinase pathway leading to effects on gene transcription and metabolism (Vanderkuur, Butch et al. 1997). GH also stimulates phosphorylation of the insulin receptor substrates 1, 2, 3 (IRS-1, 2, 3) with subsequent activation of the phosphoinositol-3-kinase (PI3K) resulting in stimulation of glucose transport (Souza, Frick et al. 1994).

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