Growth hormone-mediated JAK/STAT signal transduction. GH activates several signaling pathways via JAK2, including the JAK/STAT pathway [, ]. Binding of GH to its receptor (GHR) activates JAK2, which then self-phosphorylates. This is followed by phosphorylation of the GHR and, subsequently, STAT 1a, STAT 3, STAT 5a, and STAT 5b, members of a larger family of cytoplasmic transcription factors. These phosphorylated STATs form dimers that enter the nucleus, where they bind to specific DNA sequences and activate their target genes, IGF-1 and some suppressors of cytokine signaling (SOCS). Deletion of STAT5 expression leads to retarded body growth, and STAT5b is required for GH-mediated IGF-1 gene expression. In renal failure phosphorylation of JAK2 and the downstream signaling molecules STAT5, STAT3, and STAT1 is impaired, as are the nuclear levels of phosphorylated STAT proteins. This important cause of uremic GH resistance may result, in part, from up-regulation of SOCS2 and SOCS3 expression with suppressed GH signaling and also from increased protein tyrosine phosphatase activity, with enhanced dephosphorylation and deactivation of the signaling proteins. Reprinted from [] with permission
