Growth hormone receptor signaling (Homo sapiens)

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Bibliography

1. Lebrun JJ, Ali S, Sofer L, Ullrich A, Kelly PA.; ''Prolactin-induced proliferation of Nb2 cells involves tyrosine phosphorylation of the prolactin receptor and its associated tyrosine kinase JAK2.''; PubMed Europe PMC Scholia
2. Postel-Vinay MC, Finidori J.; ''Growth hormone receptor: structure and signal transduction.''; PubMed Europe PMC Scholia
3. Deng L, He K, Wang X, Yang N, Thangavel C, Jiang J, Fuchs SY, Frank SJ.; ''Determinants of growth hormone receptor down-regulation.''; PubMed Europe PMC Scholia
4. Kim B, Cheng HL, Margolis B, Feldman EL.; ''Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling.''; PubMed Europe PMC Scholia
5. Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMed Europe PMC Scholia
6. Rowland JE, Lichanska AM, Kerr LM, White M, d'Aniello EM, Maher SL, Brown R, Teasdale RD, Noakes PG, Waters MJ.; ''In vivo analysis of growth hormone receptor signaling domains and their associated transcripts.''; PubMed Europe PMC Scholia
7. Rowlinson SW, Yoshizato H, Barclay JL, Brooks AJ, Behncken SN, Kerr LM, Millard K, Palethorpe K, Nielsen K, Clyde-Smith J, Hancock JF, Waters MJ.; ''An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway.''; PubMed Europe PMC Scholia
8. Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, Carter-Su C.; ''Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase.''; PubMed Europe PMC Scholia
9. Poger D, Mark AE.; ''Turning the growth hormone receptor on: evidence that hormone binding induces subunit rotation.''; PubMed Europe PMC Scholia
10. Foster CM, Shafer JA, Rozsa FW, Wang XY, Lewis SD, Renken DA, Natale JE, Schwartz J, Carter-Su C.; ''Growth hormone promoted tyrosyl phosphorylation of growth hormone receptors in murine 3T3-F442A fibroblasts and adipocytes.''; PubMed Europe PMC Scholia
11. Silva CM, Day RN, Weber MJ, Thorner MO.; ''Human growth hormone (GH) receptor is characterized as the 134-kilodalton tyrosine-phosphorylated protein activated by GH treatment in IM-9 cells.''; PubMed Europe PMC Scholia
12. Behrmann I, Janzen C, Gerhartz C, Schmitz-Van de Leur H, Hermanns H, Heesel B, Graeve L, Horn F, Tavernier J, Heinrich PC.; ''A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation.''; PubMed Europe PMC Scholia
13. Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA.; ''Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity.''; PubMed Europe PMC Scholia
14. Ross RJ, Esposito N, Shen XY, Von Laue S, Chew SL, Dobson PR, Postel-Vinay MC, Finidori J.; ''A short isoform of the human growth hormone receptor functions as a dominant negative inhibitor of the full-length receptor and generates large amounts of binding protein.''; PubMed Europe PMC Scholia
15. Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE, Lavan BE.; ''Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells.''; PubMed Europe PMC Scholia
16. Cunningham BC, Ultsch M, De Vos AM, Mulkerrin MG, Clauser KR, Wells JA.; ''Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule.''; PubMed Europe PMC Scholia
17. Rosenthal LA, Winestock KD, Finbloom DS.; ''IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.''; PubMed Europe PMC Scholia
18. Brooks AJ, Waters MJ.; ''The growth hormone receptor: mechanism of activation and clinical implications.''; PubMed Europe PMC Scholia
19. Pasquali C, Curchod ML, Wälchli S, Espanel X, Guerrier M, Arigoni F, Strous G, Hooft van Huijsduijnen R.; ''Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor.''; PubMed Europe PMC Scholia
20. Leung DW, Spencer SA, Cachianes G, Hammonds RG, Collins C, Henzel WJ, Barnard R, Waters MJ, Wood WI.; ''Growth hormone receptor and serum binding protein: purification, cloning and expression.''; PubMed Europe PMC Scholia
21. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K.; ''The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.''; PubMed Europe PMC Scholia
22. de Vos AM, Ultsch M, Kossiakoff AA.; ''Human growth hormone and extracellular domain of its receptor: crystal structure of the complex.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ADAM17	Protein	P78536 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated cytokine-like hormone receptors, p	Complex	REACT_111453 (Reactome)
Activated cytokine-like hormone receptors	Complex	REACT_111865 (Reactome)
CIS, SOCS1-3	Protein	REACT_111344 (Reactome)
CISH	Protein	Q9NSE2 (Uniprot-TrEMBL)
CSH1	Protein	P01243 (Uniprot-TrEMBL)
ERK	Protein	REACT_24485 (Reactome)
GH1	Protein	P01241 (Uniprot-TrEMBL)	Growth hormone is typically used to refer to the endogenous hormone - somatotropin is reserved for synthetic hormone produced by recombinant technology.
GH2	Protein	P01242 (Uniprot-TrEMBL)
GHBP GH	Complex	REACT_111655 (Reactome)
GHBP GHR	Complex	REACT_111483 (Reactome)
GHR activated	Protein	P10912 (Uniprot-TrEMBL)
GHR	Protein	P10912 (Uniprot-TrEMBL)
Growth Hormone Activated Growth Hormone Receptor p	Complex	REACT_111267 (Reactome)
Growth Hormone Activated Growth Hormone Receptor p	Complex	REACT_111346 (Reactome)
Growth Hormone Activated Growth Hormone Receptor- p	Complex	REACT_111571 (Reactome)
Growth Hormone Activated Growth Hormone Receptor-JAK2 dimer	Complex	REACT_111254 (Reactome)
Growth Hormone Growth Hormone Receptor-JAK2 dimer	Complex	REACT_111685 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer SHP1	Complex	REACT_111822 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer SHP2	Complex	REACT_111779 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Complex	REACT_111336 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Complex	REACT_111463 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Complex	REACT_111499 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Complex	REACT_111649 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Complex	REACT_111716 (Reactome)
Growth Hormone Growth Hormone Receptor-JAK2 dimer LYN	Complex	REACT_111316 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Complex	REACT_111332 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Complex	REACT_111581 (Reactome)
Growth Hormone p	Complex	REACT_111750 (Reactome)
Growth Hormone Receptor JAK2	Complex	REACT_111660 (Reactome)
Growth Hormone Receptor-JAK2 dimer	Complex	REACT_111828 (Reactome)
Growth Hormone	Protein	REACT_111755 (Reactome)
Growth hormone oligomer		REACT_111776 (Reactome)
H2O	Metabolite	CHEBI:15377 (ChEBI)
IRS1,2	Protein	REACT_12744 (Reactome)	The proteins mentioned here are examples of IRS family members acting as indicated for IRS. More family members are to be confirmed and added in the future.
JAK2	Protein	O60674 (Uniprot-TrEMBL)
JAK2	Protein	O60674 (Uniprot-TrEMBL)
LYN	Protein	P07948 (Uniprot-TrEMBL)
PRL	Protein	P01236 (Uniprot-TrEMBL)
PRLR	Protein	P16471 (Uniprot-TrEMBL)
PRLR ligands Activated PRLR JAK2 dimer SH2B1 beta	Complex	REACT_116998 (Reactome)
PTPN1	Protein	P18031 (Uniprot-TrEMBL)
PTPN1	Protein	P18031 (Uniprot-TrEMBL)
PTPN6	Protein	P29350 (Uniprot-TrEMBL)
PTPN6	Protein	P29350 (Uniprot-TrEMBL)
Phospho-ERK	Protein	REACT_24269 (Reactome)
Pi	Metabolite	CHEBI:18367 (ChEBI)
SH2B1-2	Protein	Q9NRF2-2 (Uniprot-TrEMBL)
SOCS1	Protein	O15524 (Uniprot-TrEMBL)
SOCS2	Protein	O14508 (Uniprot-TrEMBL)
SOCS3	Protein	O14543 (Uniprot-TrEMBL)
SOCS	Protein	REACT_111744 (Reactome)
STAT1, STAT3	Protein	REACT_27778 (Reactome)
STAT1-1	Protein	P42224-1 (Uniprot-TrEMBL)
STAT3	Protein	P40763 (Uniprot-TrEMBL)
STAT5A	Protein	P42229 (Uniprot-TrEMBL)
STAT5B	Protein	P51692 (Uniprot-TrEMBL)
STAT5	Protein	REACT_24211 (Reactome)
Zn2+	Metabolite	CHEBI:29105 (ChEBI)
p-5Y-GHR	Protein	P10912 (Uniprot-TrEMBL)
p-IRS1,2	Protein	REACT_4523 (Reactome)
p-STAT5 dimer		REACT_24109 (Reactome)
p-STAT5 dimer		REACT_24289 (Reactome)
p-STAT5A/B	Protein	REACT_24299 (Reactome)
p-Y1007-JAK2	Protein	O60674 (Uniprot-TrEMBL)
p-Y332,Y487,Y627-GHR	Protein	P10912 (Uniprot-TrEMBL)
p-Y694-STAT5A	Protein	P42229 (Uniprot-TrEMBL)
p-Y699-STAT5B	Protein	P51692 (Uniprot-TrEMBL)
p-Y705-STAT3	Protein	P40763 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
ADAM17		mim-catalysis	REACT_111197 (Reactome)
	ADP	Arrow	REACT_111076 (Reactome)
	ADP	Arrow	REACT_111147 (Reactome)
	ADP	Arrow	REACT_111190 (Reactome)
	ADP	Arrow	REACT_111207 (Reactome)
	ADP	Arrow	REACT_111218 (Reactome)
	ADP	Arrow	REACT_111235 (Reactome)
ATP			REACT_111076 (Reactome)
ATP			REACT_111147 (Reactome)
ATP			REACT_111190 (Reactome)
ATP			REACT_111207 (Reactome)
ATP			REACT_111218 (Reactome)
ATP			REACT_111235 (Reactome)
	Activated cytokine-like hormone receptors, p	Arrow	REACT_111076 (Reactome)
Activated cytokine-like hormone receptors			REACT_111076 (Reactome)
CIS, SOCS1-3			REACT_111220 (Reactome)
ERK			REACT_111235 (Reactome)
GHBP GHR		TBar	REACT_111208 (Reactome)
	GHR	Arrow	REACT_111197 (Reactome)
GHR			REACT_111052 (Reactome)
GHR			REACT_111073 (Reactome)
GHR			REACT_111114 (Reactome)
	Growth Hormone Activated Growth Hormone Receptor p	Arrow	REACT_111207 (Reactome)
Growth Hormone Activated Growth Hormone Receptor p			REACT_111207 (Reactome)
Growth Hormone Activated Growth Hormone Receptor p		mim-catalysis	REACT_111207 (Reactome)
Growth Hormone Activated Growth Hormone Receptor- p			REACT_111047 (Reactome)
Growth Hormone Activated Growth Hormone Receptor- p			REACT_111147 (Reactome)
Growth Hormone Activated Growth Hormone Receptor- p		mim-catalysis	REACT_111147 (Reactome)
Growth Hormone Activated Growth Hormone Receptor- p		mim-catalysis	REACT_111190 (Reactome)
Growth Hormone Growth Hormone Receptor-JAK2 dimer			REACT_111139 (Reactome)
	Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer SHP1	Arrow	REACT_111048 (Reactome)
	Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer SHP2	Arrow	REACT_111128 (Reactome)
	Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Arrow	REACT_111147 (Reactome)
	Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Arrow	REACT_111224 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111061 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111128 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111198 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111212 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111219 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111220 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111226 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p		mim-catalysis	REACT_111048 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p		mim-catalysis	REACT_111061 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p		mim-catalysis	REACT_111128 (Reactome)
Growth Hormone Growth Hormone Receptor-JAK2 dimer LYN		mim-catalysis	REACT_111235 (Reactome)
	Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p	Arrow	REACT_111218 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p			REACT_111218 (Reactome)
Growth Hormone Tyrosine phosphorylated Growth Hormone Receptor-p		mim-catalysis	REACT_111218 (Reactome)
	Growth Hormone p	Arrow	REACT_111061 (Reactome)
Growth Hormone Receptor-JAK2 dimer			REACT_111053 (Reactome)
Growth Hormone			REACT_111053 (Reactome)
Growth Hormone			REACT_111114 (Reactome)
H2O			REACT_111061 (Reactome)
H2O			REACT_111128 (Reactome)
IRS1,2			REACT_111190 (Reactome)
JAK2			REACT_111052 (Reactome)
LYN			REACT_111139 (Reactome)
PRLR ligands Activated PRLR JAK2 dimer SH2B1 beta		Arrow	REACT_111076 (Reactome)
PTPN1			REACT_111219 (Reactome)
PTPN6			REACT_111226 (Reactome)
	Phospho-ERK	Arrow	REACT_111235 (Reactome)
	Pi	Arrow	REACT_111048 (Reactome)
	Pi	Arrow	REACT_111061 (Reactome)
	Pi	Arrow	REACT_111128 (Reactome)
			REACT_111047 (Reactome)	JAK2 is believed to bind STAT1 and STAT3 directly in response to GH, as opposed to STAT5 which binds to phosphorylated tyrosine residues in the distal portion of the GHR cytoplasmic region (Smit et al. 1996). When associated with the prolactin receptor JAK2 is able to bind STAT1, STAT3 and STAT5 (DaSilva et al. 1996). Smit et al. identified mouse GHR residues Y341 (human Y332) and Y346 (not conserved in human) as required for STAT1, 3, and maximal STAT5 activation.
			REACT_111048 (Reactome)	SHP1 (PTPN6) dephosphorylates GH-activated JAK2, limiting the duration of signaling (Hackett et al. 1999).
			REACT_111052 (Reactome)	JAKs bind to the box1 motif (residues 297-305) of the Growth Hormone Receptor (GHR) (Argetsinger et al. 1993), a proline-rich region just inside the cell membrane. Binding is mediated largely by the JAK N-terminal FERM domain (Frank et al. 1995, He et al. 2003). JAK 2 binding enhances the stability of GHR (He et al. 2005).
			REACT_111053 (Reactome)	The growth hormone receptor (GHR) belongs to the superfamily of transmembrane proteins that includes the prolactin receptor and a number of class 1 cytokine receptors. It exists in two forms, full-length membrane-bound receptor with a single transmembrane region, and growth hormone binding protein (GHBP), a shorter soluble form corresponding to the extracellular domain of the full-length receptor. In rodents GHBP is encoded by a specific mRNA variant while in humans it results from proteolytic cleavage of the membrane receptor by a metalloprotease. The classical view is that growth hormone sequentially binds 2 molecules of GHR inducing dimerization, but it is now widely accepted that GHR dimers exist prior to ligand binding (Poger & Mark 2010).
			REACT_111061 (Reactome)	PTP1B induces the dephosphorylation of GHR (Pasquali et al. 2003).
			REACT_111071 (Reactome)	Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms. The peptide is encoded by 2 genes, GH1 and GH2, both give rise to multiple variant forms. Post-translational modification including oligomerization increases the variation (Baumann 2009). Approximately 14% of circulating human Growth Hormone (GH) is in dimer or oligomer form, this number varying from 0 to 100% (Kublickas et al. 2006). The biological activity of these oligomeric forms is variably diminished when compared to the monomer (Baumann 2009).
			REACT_111073 (Reactome)	GHBP, the ectodomain of GHR cleaved from membrane-bound GHR can form a heterodimer with GHR. This is not capable of signaling and may be a negative regulatory influence. GHBP can also inhibit signaling by competing with the full length receptor for GH binding.
			REACT_111076 (Reactome)	Similar models explain JAK activation by the cytokine-like hormone receptors (GHR and PRLR) and interleukin receptors. JAK2 activation is believed to occur as mutual transactivation whereby JAK2 bound to one receptor chain phosphorylates JAK2 bound to the other receptor chain in the dimeric receptor. Transactivation is widely accepted (Herrington & Carter-Su 2001) having been originally proposed in the 1990's (Quelle et al. 1994, Hou et al. 2002). JAK phosphorylation is thought to lock the kinase domain in an active state; prior to this JAK2 is held in an inactive state by interactions between its kinase and pseudokinase domains (Giordanetto & Kroemer 2002). Although there are structures of JAK kinase domains (e.g. Lucet et al. 2006), no complete JAK structures are available and the activation mechanism remains poorly understood (Brooks & Waters 2010). The trigger for JAK activation is believed to be a conformational change in the receptor when ligand is bound, leading to a rotation of the cytoplasmic regions which brings the catalytic domains of bound JAK2 molecules into close proximity and frees them from inhibition by the pseudokinase domains. Supporting observations for cytokine-like hormone receptors include: JAK2 becomes tyrosine phosphorylated as a consequence of GHR activation by GH (Argetsinger et al. 1993); JAK2 is activated following PRLR activation (Campbell et al. 1994, Rui et al. 1994); forced dimerization of GH receptor domains is sufficient to activate signaling (Behncken et al. 2000); phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006); JAK autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the Y1007 phosphorylation is represented in this reaction.
			REACT_111114 (Reactome)	GHBP is the ectodomain of GHR, cleaved from membrane-bound GHR in man and rabbits, while in rodents it is derived from an alternatively spliced mRNA. GHBP circulates in nanomolar concentrations, sufficient to complex approximately 50% of plasma GH (Baumann et al. 1988). GHBP can compete for GHR binding, inhibiting GHR signaling (Lim et al. 1990), and generates 'unproductive' heterodimers with GHR at the cell surface (Ross et al. 1997), but GHBP can also increase GH biological activity by prolonging its half-life (Baumann et al. 1987). The net effect of GHBP may depend on the relative concentrations of circulating GH and GHBP (Lim et al. 1990, Barnard & Waters 1997), the overall effect is postulated to be stabilization of GH signaling (Veldhuis et al. 1993). GHBP appears to be positively linked to GH action. It has been suggested that plasma GHBP levels reflect tissue concentrations of GHR, but this remains to be proven.
			REACT_111128 (Reactome)	PTP1B dephosphorylates JAK2 (Gu et al. 2003), limiting ligand-dependent signaling.
			REACT_111139 (Reactome)	There is accumulating evidence that GH signalling utilises a Src family tyrosine kinase independently of JAK2, and that this is linked to activation of extracellular regulated kinases (ERKs) 1 and 2 (p44/42 MAPK). The relative strengths of these signaling pathways probably depends on cell type and may be mediated by conformational changes that are a consequence of ligand binding (Rowlinson et al. 2007). In NIH-3T3 cells GH activated c-Src, which in turn activated ERK1/2 via a pathway involving the activation of the Ras-like small GTPases RalA and RalB, leading to Elk-1 mediated transcription (Zhu et al. 2002). JAK2 and c-Src were both found to activate the Ras-like small GTPases Rap1 and Rap2 which inhibit RalA mediated activation of ERK1/2 (Ling et al. 2003). Src kinase inhibition was found to block ERK activation by GH. The major contributing kinase was identified as Lyn, which was found to co-immunoprecipitate with GHR and bind to the proximal 150 residues of the cytoplasmic domain (Rowlinson et al. 2007).
			REACT_111147 (Reactome)	Activated JAK2 phosphorylates multiple tyrosine residues on GHR (Argetsinger et al. 1993, VanderKuur et al. 1994) including Y332 (VanderKuur 1995), Y487, Y534, Y566, and Y627 (Wang et al. 1996). Wang et al. using the porcine receptor found that phosphorylation at any of the positions they examined (all conserved in humans) was sufficient for STAT5 phosphorylation. While STAT5 activation requires phosphorylation of the distal region of GHR, this has no effect on STAT1 or STAT3 activation (Yi et al. 1996) suggesting different mechanisms. Mutation of Y332 to F in a truncated form of GHR with only the first 54 residues of the cytoplasmic domain had no effect on JAK2 activation or cell proliferation presumed to be mediated by ERK (Wang et al. 1995) so the significance of phosphorylation at this position is unclear. SHP2 binds to Y595 of rat GHR (identical numbering in humans) and to a lesser extent Y487; mutation of these residues impairs the association (Stofega et al. 2000). SOCS3 binds to rat GHR Y333 (equivalent of human Y332), Y338 (not conserved in humans) (Ram & Waxman 1999) and Y487 (Hansen et al. 1999). SOCS-1 has been implicated as a direct inhibitor of JAK kinases (Yasukawa et al. 1999). This reaction represents the phosphorylation of all GHR tyrosines known to be phosphorylated by JAK2.
			REACT_111166 (Reactome)	Classical models of GHR activation suggest that GH binds sequentially to two GHR molecules, leading to receptor dimerization and activation. More recently, evidence from FRET, BRET, Co-IP (Brown et al. 2005) and molecular simulations (Poger & Mark 2010) suggest that dimerization occurs before ligand binding, and that activation is a consequence of conformational changes caused by ligand binding, namely a relative rotation of the receptor dimer so that the catalytic domains of JAK2 molecules bound to the cytoplasmic tails are brought into close proximity and are consequently able to phosphorylate each other (Rowlinson et al. 2008). Realignment of the receptor subunits and consequent JAK2 activation is supported by crystal structures of the related erythropoietin receptor (Livnah et al. 1999); similar proposals have been made for many receptors, including the prolactin and erythropoietin receptors (Brooks & Waters 2010).
			REACT_111190 (Reactome)	GH has short term effects that mimic the actions of insulin in tissues that have been deprived of GH, including increased amino acid transport, glucose transport, and lipogenesis (Davidson 1987). GH and insulin have overlapping signaling pathways (Dominici et al. 2005). GH stimulates tyrosyl phosphorylation of insulin receptor substrate-1 (IRS-1) (Souza et al. 1994, Thirone et al. 1999), and IRS-2 (Argetsinger et al. 1996, Thirone et al. 1999), although more modestly than insulin or IGF-1. Tyrosyl phosphorylation of IRS-1 and IRS-2 in response to insulin provides binding sites for specific proteins containing SH2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K), tyrosine phosphatase SHP2, and Grb2. This is one of several mechanisms proposed to explain the stimulatory effect of GH on the PI3-kinase/Akt pathway (Jin et al. 2008). GH promotes the binding of the 85-kDa regulatory subunit of PI3K to IRS-1 and IRS-2 in cultured cells (Ridderstrale et al. 1995, Argetsinger et al. 1995, 1996). Studies using truncated or mutated GHRs suggest that tyrosyl phosphorylation of IRS-1, IRS-2, and Shc is dependent on JAK2 activation (Argetsinger et al. 1995, 1996, VanderKuur et al. 1995). Despite a strong correlation between JAK2 activation and IRS phosphorylation it is not clear whether there is a direct association. JAK2 has been reported to interact directly with IRS in response to angiotensin II (Velloso et al. 1996) but also reported to interact indirectly via SH2B in response to leptin (Duan et al.2004).
			REACT_111197 (Reactome)	Approximately half of circulating GH is bound to Growth Hormone Binding Protein ((GHBP) Herington et al. 1986), a soluble fragment of the Growth Hormone Receptor (Baumann et al. 1986) formed when the extracellular region is proteolytically cleaved (Leung et al. 1987). This cleavage is mediated by metalloproteases such as TACE (ADAM17, Zhang et al. 2000). The membrane-bound remnant is subsequently degraded by the gamma-secretase complex (Cowan et al. 2005).
			REACT_111198 (Reactome)	SOCS1 can bind JAK2 and inhibit JAK kinase activity (Yasukawa et al. 1999). SOCS3 also inhibits JAK2 kinase activity (Sasaki et al. 1999) while all of SOCS1 -3 and CIS inhibit GHR signaling (Ram & Waxman 1999, Nicholson et al. 2000). This is not thought to be simply the outcome of binding competition between SOCS and STAT5, but a direct action of SOCS on JAK2 (Ram & Waxman 1999). Although SOCS are known to be ubiquitin ligases (Kamura et al. 2004), ubiquitin ligase activity on JAK2 or GHR has not been demonstrated and a role for SOCS in the ubiquitination of these proteins has been questioned (Flores-Morales et al. 2006). An alternative model suggested by the observation that SOCS3 strongly inhibits JAK2 only in the presence of GHR proposes that SOCS serve as an inhibitory 'bridge' by binding simultaneously to GHR and JAK2 (Ram & Waxman 1999).
			REACT_111207 (Reactome)	GH stimulated tyrosyl phosphorylation of Stats 1, 3, and 5 in CHO cells expressing GHR constructs that bind JAK2 but not in CHO cells expressing GHR constructs that do not bind JAK2 (Smit et al. 1996). STAT5 phosphorylation was greatly reduced in GHR mutants with the distal region of the cytoplasmic tail removed and by mutation of distal GHR tyrosine residues to phenylalanine but this had no effect on STAT1/STAT3 phosphorylation, suggesting that the latter interact with JAK2 directly.
			REACT_111208 (Reactome)	The growth hormone receptor forms dimers (Cunningham et al. 1991) that subsequently signal via JAK2 (Argetsinger et al. 1993). Early studies suggested that dimerization occured following ligand binding, but it is now generally accepted that dimerization is independent of ligand binding and involves the transmembrane and juxtamembrane domains (van den Eijnden et al. 2006, Brown et al. 2005).
			REACT_111212 (Reactome)	JAK2 is required for GH-mediated phosphorylation of STATs 1,3,5A and 5B (Smit et al.1996). Some STAT activation may be mediated by direct association of JAK and STAT but maximal activation requires binding of STATs to phosphorylated tyrosines of the receptor (Smit et al. 1996, Lichanska & Waters 2006). Studies using mouse GHR truncated at K391, equivalent to human K380, suggest that STAT5 signaling is mediated by distal tyrosines, with 70% of the signaling lost if the receptor is truncated at P569, equivalent to human P558 (Rowland et al. 2005). Wang et al. (1996) using the porcine receptor found that phosphorylation at any one of the positions Y487, Y534, Y566 or Y627 (numbering identical in humans) was sufficient to allow STAT5 phosphorylation. Smit et al. (1996) identified mouse residues Y341 (human Y332) and Y346 (not conserved in human) as required for STAT1, 3, and maximal STAT5 activation.
			REACT_111213 (Reactome)	Cell surface levels of GHR are the primary determinant of GH responsiveness. This is modulated partly by endocytosis and lysosomal degradation. This downregulation is strongly inhibited by the association of JAK2 with the receptor, and by GH if JAK2 is prevented from signaling, but markedly enhanced by GH if JAK2 is kinase active. GH down-regulation also requires GHR tyrosine phosphorylation (Deng et al. 2007) and is believed to be mediated by GHR ubiquitination and proteasomal degradation.
			REACT_111218 (Reactome)	Stat5 tyrosine phosphorylation was seen in response to GH in CHO cells expressing mouse GHR forms capable of binding JAK2 (Smit et al. 1996). Similar results were obtained using the porcine receptor (Wang et al. 1996). Thus Jak2 phosphorylates Stat5, the phosphorylated monomers form dimers and translocate to the nucleus (Darnell et al. 1994).
			REACT_111219 (Reactome)	PTP1B has been shown to associate with GH-dependent phosphorylated GHR and induce its dephosphorylation (Pasquali et al. 2003). It can also dephosphorylate JAK2 (Gu et al. 2003). Both have the effect of reducing JAK signaling.
			REACT_111220 (Reactome)	Suppressor of Cytokine Signaling (SOCS) proteins inhibit the GH signal; SOCS2 null mice exhibit giantism (Greenhalgh et al. 2005). Suppressor of Cytokine Signaling (SOCS)1-3, and the realted Cytokine-inducible SH2-containing protein (CIS) all bind tyrosine-phosphorylated GHR; SOCS1 can also binds GHR in the absence of tyrosine phosphorylation (Ram & Waxman 1999, Hansen et al. 1999). SOCS3 binding has been mapped to phosphorylated tyrosines Y338, Y333 (Ram & Waxman 1999), and Y487 (Hansen et al. 1999) in the membrane proximal region of the receptor while SOCS2 and CIS bind to residues Y487 and Y595 (Uyttendaele et al. 2007). SOCS2/3/CIS may compete with STAT5 for GHR binding at these sites but in the case of SOCS3 also appears to act by inhibiting JAK2 directly (Yasukawa et al. 1999).
			REACT_111224 (Reactome)	Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believed to occur following release of the phosphorylated monomers from the receptor complex and is typically represented in this manner (e.g. Turkson & Jove 2000).
			REACT_111226 (Reactome)	SHP1 binds GH-activated JAK2 and controls the duration of GH-dependent JAK2 phosphorylation in the liver, consequently hepatic GH signaling is prolonged in mice lacking SHP1 (Hackett et al. 1999).
			REACT_111235 (Reactome)	The activation of Lyn by GHR is thought to indirectly activate ERK. Mutations of GHR predicted to disable a conformational change brought about by GH binding impaired ERK signaling but not JAK2/STAT5 signaling. ERK signaling was demonstrated to involve the Src family kinase Lyn (Rowlinson et al. 2008) and suggested to involve Src kinase dependent activation of Phospholipase C gamma and thereby Ras, similar to a mechanism proposed by Bivona et al. (2003). ERK activation mechanisms involving Src kinases and PLCgamma have been reported for the erythropoietin, thrombopoietin and prolactin receptors (Brooks & Waters 2010).
			REACT_23774 (Reactome)	STAT5A and STAT5B dimers bind to similar core gamma-interferon activated sequence (GAS) motifs (Soldaini et al., 2000). STAT5a/b also form homo- and hetero-tetramers with distinct or expanded DNA-binding properties. Genes that are regulated by STAT5 include IL2RA (John et al. 1996), TNFSF11 (RANKL), Connexin-26 (GJB2) and Cyclin D1 (Hennighausen & Robinson, 2005). A comprehensive listing of hepatic STAT5b regulated genes is available from microarray/STAT5b knockout mice (Clodfelter et al. 2006), and similarly for STAT5-dependent genes regulated by the GH receptor (Rowland et al. 2005, Barclay et al. 2011).
			REACT_23827 (Reactome)	The STAT5a and STAT5b forms are encoded by 2 closely-related genes. They are thought to be present largely as monomers in unstimulated cells but rapidly form homo- and hetero-dimers upon stimulation (Cella et al. 1998). Tyrosine phosphorylation of STAT monomers allows dimers to form through reciprocal phosphotyrosine-SH2 interactions. The dimers translocate to the nucleus and bind to STAT-specific DNA-response elements of target genes to induce gene transcription (Baker et al.2007). STAT5a/b homo- and hetero-tetramers have also been shown to occur downstream of IL-2 and may have a distinct or expanded target repertoire from STAT5a/b dimers. Although STAT5a and STAT5b are highly homologous at the DNA and protein levels, each has unique funcions, as demonstrated by studies comparing mice lacking one isoform or the other. However, it is also known that STAT5a and STAT5b share a number of functions and that the phenotype of mice lacking both STAT5a and STAT5b is more severe than those lacking either one individually, which suggest that there may be some redundancy or that they cooperate in order to achieve the full spectrum of STAT5-dependent activities (Moriggl et al. 1999, Teglund et al. 1998).
SOCS			REACT_111198 (Reactome)
STAT1, STAT3			REACT_111047 (Reactome)
STAT5			REACT_111212 (Reactome)
	p-IRS1,2	Arrow	REACT_111190 (Reactome)
	p-STAT5A/B	Arrow	REACT_111224 (Reactome)