Growth hormone receptor (GHR) signaling (WP2891)

Signal transducers and activators transcription (STAT) proteins are cytoplasmic transcription factors containing SH2 domains that bind to the activated GHR and become phosphorylated by JAK2. activation of the GH receptor can also initiate signal transduction via the Ras/Raf/mitogen-activated protein (MAP) kinase pathway leading to effects on gene transcription and metabolism.GH also stimulates phosphorylation of the insulin receptor substrates 1,2,3(IRS-1,2,3,4)with subsequent activation of the phosphoinositol-3-kinase (PI3K) resulting in stimulation of glucose transport. This pathway was based on the below review articles.
Initiation of GH signaling requires that a single GH molecule binds to two GHR monomers causing receptor dimerization. Proper dimerization occurs by sequential binding of the receptor to a high affinity site in GH followed by recruitment of the second receptor to a low affinity site (Cunningham, Ultsch et al. 1991). However, some evidence suggest the existence of preformed, unliganded receptor dimers that are activated by a ligand-induced change in receptor conformation (Behncken and Waters 1999; Frank 2002). In accordance with the receptor dimerization mechanism, dose- response experiments give rise to biphasic, bell-shaped kinetics (Ilondo, Damholt et al. 1994). GHR dimerization and ligand-induced conformational change bring the intracellular receptor domains into close proximity whereby downstream signaling events are triggered. Receptor-associated tyrosine kinase JAK2 (Janus kinase 2) is activated (Argetsinger, Campbell et al. 1993) and phosphorylates cytoplasmic domains of GHRs on tyrosine residues, thereby creating docking sites for SH2 (src homology 2) containing proteins (Herrington and Carter-Su 2001). Signal transducers and activators of transcription (STAT) proteins are cytoplasmic transcription factors containing SH2 domains that bind to the activated GHR and become phosphorylated by JAK2. Phosphorylated members of the STAT family homo- or heterodimerize and translocate to the nucleus where they bind to specific DNA target elements and activate gene transcription (Herrington, Smit et al. 2000). Activation of the GH receptor can also initiate signal transduction via the Ras/Raf/mitogen-activated protein (MAP) kinase pathway leading to effects on gene transcription and metabolism (Vanderkuur, Butch et al. 1997). GH also stimulates phosphorylation of the insulin receptor substrates 1, 2, 3 (IRS-1, 2, 3) with subsequent activation of the phosphoinositol-3-kinase (PI3K) resulting in stimulation of glucose transport (Souza, Frick et al. 1994).
last edited

Authors

Zari, Evelo, Khanspers, Jmelius, and Eweitz

Cited In

Organism

Bos taurus

Communities

Annotations

Pathway Ontology: signaling pathway

Participants

Label Type Compact Identifier
SHC1 GeneProduct ensembl:ENSBTAG00000019838
IRS1 GeneProduct ncbigene:538598
GHR GeneProduct ncbigene:280805
MAPK7 GeneProduct ncbigene:537703
GH1 GeneProduct ncbigene:280804
MAPK11 GeneProduct ncbigene:618906
STAT5B GeneProduct ncbigene:282376
MAPK9 GeneProduct ncbigene:534125
IRS2 GeneProduct ensembl:ENSBTAG00000012019
IRS4 GeneProduct ncbigene:514607
PIK3R4 GeneProduct ncbigene:507414
PIK3R1 GeneProduct ncbigene:282307
MAPK1 GeneProduct ncbigene:327672
PIK3CD GeneProduct ncbigene:504531
MAPK13 GeneProduct ncbigene:535327
PIK3CA GeneProduct ncbigene:282306
PIK3R2 GeneProduct ncbigene:282308
PIK3R6 GeneProduct ncbigene:515621
MAPK6 GeneProduct ncbigene:538094
MAPK8 GeneProduct ncbigene:539941
JAK2 GeneProduct ncbigene:525246
SHC2 GeneProduct ensembl:ENSBTAG00000016072
STAT4 GeneProduct ncbigene:515988
IRS3 GeneProduct None
STAT2 GeneProduct ncbigene:511023
STAT3 GeneProduct ncbigene:508541
PIK3CB GeneProduct ncbigene:517948
STAT1 GeneProduct ncbigene:510814
SHC4 GeneProduct ncbigene:524734
MAPK10 GeneProduct ncbigene:537631
PIK3R5 GeneProduct ncbigene:614838
MAPK4 GeneProduct ensembl:ENSBTAG00000009907
MAPK15 GeneProduct ncbigene:512125
MAPK12 GeneProduct ncbigene:512943
MAPK14 GeneProduct ncbigene:534492
STAT6 GeneProduct ncbigene:353105
PIK3R3 GeneProduct ncbigene:286865
STAT5A GeneProduct ncbigene:282375
SHC3 GeneProduct ncbigene:512696
PIK3CG GeneProduct ncbigene:530001
MAPK3 GeneProduct ncbigene:531391
JAK2 GeneProduct ncbigene:525246

References

  1. Herrington J, Smit LS, Schwartz J, Carter-Su C. The role of STAT proteins in growth hormone signaling. Oncogene. 2000 May 15;19(21):2585–97. PubMed Europe PMC Scholia
  2. Herrington J, Carter-Su C. Signaling pathways activated by the growth hormone receptor. Trends Endocrinol Metab. 2001 Aug;12(6):252–7. PubMed Europe PMC Scholia
  3. Jiang H, Ge X. MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM--mechanism of growth hormone stimulation of skeletal muscle growth in cattle. J Anim Sci. 2014 Jan;92(1):21–9. PubMed Europe PMC Scholia