JAK2 phosphorylation of IRS-1/2 JAK2 binds STAT1/3 JAK2 phosphorylates STAT1/STAT3 Growth hormone receptor binds Lyn Lyn activates ERK STAT5 tyrosine phosphorylation Phosphorylated STAT5 is released JAK2 phosphorylation of GHR STAT5 association with GHR SOCS binding to GHR SOCS binding to JAK2 PTP1B binds the GH receptor complex Metalloprotease cleavage of GHR GHBP binds GH GHBP binds GHR GHR internalization PTP1B dephosphorylates GHR PTP1B dephosphorylates JAK2 SHP1 (PTPN6) binds JAK2 in the receptor complex SHP1 (PTPN6) dephosphorylates JAK2 Growth hormone forms dimers and oligomers Growth hormone receptor dimerizes Growth hormone receptor binds JAK2 Growth hormone binds the growth hormone receptor GH:GHR:JAK2 complex undergoes a conformational change STAT5 dimers translocate to the nucleus and bind to specific DNA sequences Phosphorylated STAT5a/b form dimers PathwayStep7153 PathwayStep7154 PathwayStep7241 PathwayStep7240 PathwayStep7245 PathwayStep7244 PathwayStep7243 PathwayStep7242 PathwayStep7239 PathwayStep7230 PathwayStep7236 PathwayStep7235 PathwayStep7238 PathwayStep7237 PathwayStep7232 PathwayStep7231 PathwayStep7234 PathwayStep7233 PathwayStep7228 PathwayStep7229 PathwayStep7227 PathwayStep7226 PathwayStep7225 PathwayStep7224 PathwayStep7223 PathwayStep7222 PathwayStep7221 PathwayStep5402 Growth hormone receptor signaling Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 GENE ONTOLOGYGO:0060397 Growth hormone (Somatotropin or GH) is a key factor in determining lean body mass, stimulating the growth and metabolism of muscle, bone and cartilage cells, while reducing body fat. It has many other roles; it acts to regulate cell growth, differentiation, apoptosis, and reorganisation of the cytoskeleton, affecting diverse processes such as cardiac function, immune function, brain function, and aging. GH also has insulin-like effects such as stimulating amino acid transport, protein synthesis, glucose transport, and lipogenesis. The growth hormone receptor (GHR) is a a member of the cytokine receptor family. When the dimeric receptor binds GH it undergoes a conformational change which leads to phosphorylation of key tyrosine residues in its cytoplasmic domains and activation of associated tyrosine kinase JAK2. This leads to recruitment of signaling molecules such as STAT5 and Src family kinases such as Lyn leading to ERK activation. The signal is attenuated by association of Suppressor of Cytokine Signaling (SOCS) proteins and SHP phosphatases which bind to or dephosphorylate specific phosphorylated tyrosines on GHR/JAK. The availability of GHR on the cell surface is regulated by at least two processes; internalization and cleavage from the suface by metalloproteases. Pubmed15601831 Pubmed17488973 Pubmed20664532 Pubmed8548048 Reactome Database ID Release 43982772 Reactome, http://www.reactome.org ReactomeREACT_111133 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 JAK2 phosphorylation