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Growth Hormone (GH) regulates postnatal longitudinal growth. It also hasseveral other functions. It decreases cholesterol and lipoproteinslevels, reduces fat tissue and increases lean body mass. GH actions aremediated by the JAK2/STAT5 signaling pathway. The manner whereby thispathway is activated has been extensively studied. There are, however,gaps in our knowledge how the pathway is silenced or negativelyregulated. Down regulation of GH signaling is related to severalinterconnected mechanisms mainly involving the internalization of GHreceptor (GHR) and the action of negative regulators such as tyrosinephosphatases and suppressors of cytokine signaling (SOCS). SOCS proteinshave recently received attention as important regulators of the JAK/STATpathway. In relation to GH, it is interesting to note that mice lackingSOCS2 (SOCS2-/-) are 40% larger that their littermates. While thisevidence suggests that SOCS2 controls GH and/or IGF-I signaling, theexact mechanism behind this action has not been defined yet. Onehypothesis is that GHR turnover is critical and that SOCS proteins takepart in this process by regulating protein breakdown throughubiquitination.The aim of this thesis was to characterize pathways that regulate GHsensitivity in liver and to evaluate the mechanism of action of SOCSproteins, particularly SOCS2, as negative regulators for GH signalingpathway.We demonstrated that the duration of GH-activated JAK2/STAT5 can beprolonged by other signaling pathways, such as the UPR (Unfolded ProteinResponse) and those regulating the actin cytoskeleton. These two pathwaystarget different steps in the down regulatory pathway involving GHRubiquitination and endocytosis. Induction of UPR decreases the degree ofGHR ubiquitination while actin cytoskeleton disruption results inaccumulation of ubiquitinated GHR. Mice lacking SOCS2 (SOCS2-/-) wereanalyzed using transcript profiling and other means to evaluate theirphenotype. We demonstrated that SOCS2-/- mice have limited similaritywith GH-overexpression models. These mice are therefore not an exactmimic of GH overproduction and instead they represent  a state of theirown  in terms of gigantic phenotypes. Crossing SOCS2-/- mice with GHdeficient dwarf mice resulted in a dwarf phenotype, indicating that thegigantism of SOCS2-/- mice depends on endogenous GH secretion. When thetwo dwarf models were compared, lack of SOCS2 resulted inhypersensitivity to GH treatment, as was demonstrated by increased growthrate and exaggerated responsiveness of hepatic GH-regulated genes. Themechanism of SOCS2 action involves its binding to GHR through thetyrosines 487 and 595 and its association to Elongin BC, probably formingan ubiquitin ligase complex that could mediate GHR ubiquitination anddegradation. In conclusion, our studies indicate that GH signaling downregulation is a tightly regulated process, involving several steps. It ismodulated by UPR, actin cytoskeleton network, SOCS proteins (particularlySOCS2), the rate of GHR ubiquitination and might include the action ofsome still unidentified proteins that could contribute to the negativeaction of SOCS2

Endoplasmic Reticulum Stress Prolongs GH-Induced Janus Kinase (JAK2)/Signal Transducer and Activator of Transcription (STAT5) Signaling Pathway