Ression(S11).Inhumans,STATmutations resultinrelativeGHinsensitivityandgrowthretardation(32).GH alsoinducesearlyresponsegenesthatprecedecellgrowthanddifferentiationsignals(33)mediatedbyCCAATenhancer inding proteinandserumresponseelementsitesonthec-fospromoter.TheGHRmayalsotranslocatetothenucleusbytheimportin /pathwayinconjunctionwithcoactivatoractivator(CoAA). Genetargetsfornuclear-mediatedGHRactionarepredominantlyproproliferative.ForcedGHRtargetingtothecellnucleus alsoenhancescellproliferationandtransformationresponsivenesstoautocrine-derivedGH.Therefore,CoAAandactivatedSTAT5 arebothrequiredforGH-dependentproproliferativeactionsof nuclearGHR(34). STAT5b mediates sexually dimorphic GH signals. Females exhibitmorefrequentGHsecretorypulsesandshorterinterpulse nadirintervals,leadingtorelativedesensitizationoffemalehepatic STAT5inductionbyGHascomparedwiththatofmales.Targeted disruptionofSTAT5bleadstomale-selectivereducedgrowthrates andlossofgender-specifichepaticgeneinduction(35). GHRinsensitivitymayoccurasaconsequenceofextracellular receptordomaincleavageaswellastoxin-inducedproteolysis,TheJournalofClinicalInvestigation http://www.Gevokizumab jci.Givinostat org Volume119 Number11 Novemberscience in medicineFigureGH action. GH binds to the GHR dimer, which undergoes internal rotation, resulting in JAK2 phosphorylation (P) and subsequent signal transduction. GH signaling is mediated by JAK2 phosphorylation of depicted signaling molecules or by JAK2-independent signaling which includes Src/ERK pathways (S42). Ligand binding to a preformed GHR dimer final results in internal rotation and subsequent phosphorylation cascades. GH targets contain IGF-I, c-fos, cell proliferation genes, glucose metabolism, and cystoskeletal proteins. GHR internalization and translocation (dotted lines) induce nuclear proproliferation genes through importin / (Imp/Imp) coactivator (CoAA) signaling. IGF-I may possibly also block GHR internalization, acting within a feedback loop. The GHR antagonist, pegvisomant, blocks GHR signaling; SRLs also attenuate GH binding and signaling (not shown).whichabrogatessignaling(S11).GHRcell-surfacetranslocation isalsodirectlyinhibitedbyIGF1,likelycontributingtoalocal feedbackloop(36)(Figure3). IGF1 IGF1,thepolypeptidetargethormoneforGH,issynthesizedin theliverandextrahepatictissues(principallybone,muscle,and kidney)andalsointhepituitaryglanditself.IGF1mediatesmost ofthegrowth-promotingactionsofGH(37).Actingatboth endocrineandparacrinelevels,IGF1exertsnegativefeedback regulationofGHsynthesisandsecretion(38).About 80 ofcirculatingIGF1originatesfromtheliver,andhigh-affinitybindingproteinsincludingIGF-bindingprotein3(IGFBP3) andacid-labilesubunit(ALS)transportandalsomediateIGF1 peptideactivitybyregulatingIGF1cell-surfacereceptoraccess (39).PMID:34235739 AsIGF1receptorsareubiquitouslyexpressed,widespread enhancedcellproliferationaswellasmetabolicactionsaretriggeredbyelevatedIGF1concentrations.IGF1actsinanendocrine fashiontomediatetissuegrowth,orlocallysynthesizedIGF1acts inanautocrine/paracrinemannertoregulatelocalGHtarget tissuegrowth.In the end,organgrowthresponsestoIGF1are determinedbytheintrinsicreplicativepotentialoflocaltissues. ObservationsthatdoublymutantGhr gf1 iceexhibitmore severegrowthretardationthananimalswitheithersingle-gene deletionaloneindicatethatanabolicactionsofGH,especiallyon muscle,mayalsobedistinctivelydirectandnotnecessarilyIGF1 dependent(40).GHactsdirectlytoinducegerminalepiphyseal cells,whileIGF1actstoinducechondrocyteproliferation(41), andbasedonresultsderivedfrom.
