An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway.
The growth and metabolic actions of growth hormone (GH) are believed to be mediated through the GH receptor (GHR) by JAK2 activation. The GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Based on the crystal structures, we identify a conformational change in the F'G' loop of the lower cytokine module, which results from binding of hGH but not G120R hGH antagonist. Mutations disabling this conformational change cause impairment of ERK but not JAK2 and STAT5 activation by the GHR in FDC-P1 cells. This results from the use of two associated tyrosine kinases by the GHR, with JAK2 activating STAT5, and Lyn activating ERK1/2. We provide evidence that Lyn signals through phospholipase C gamma, leading to activation of Ras. Accordingly, mice with mutations in the JAK2 association motif respond to GH with activation of hepatic Src and ERK1/2, but not JAK2/STAT5. We suggest that F'G' loop movement alters the signalling choice between JAK2 and a Src family kinase by regulating TMD realignment. Our findings could explain debilitated ERK but not STAT5 signalling in some GH-resistant dwarfs and suggest pathway-specific cytokine agonists.
Rowlinson
Scott W
SW
Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, St Lucia 4072, Australia.
Yoshizato
Hideo
H
Barclay
Johanna L
JL
Brooks
Andrew J
AJ
Behncken
Stuart N
SN
Kerr
Linda M
LM
Millard
Kirstin
K
Palethorpe
Kathryn
K
Nielsen
Katherine
K
Clyde-Smith
Jodie
J
Hancock
John F
JF
Waters
Michael J
MJ
D000818:Animals; D019281:Dimerization; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008968:Molecular Conformation; D051966:Phospholipase C gamma / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011817:Rabbits; D011986:Receptors, Somatotropin / Q000819:agonists* / Q000737:chemistry*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051966:Phospholipase C gamma; D018631:ras Proteins