US EPA

7045709 

Journal Article 

An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway 

Rowlinson, SW; Clyde-Smith, J; Hancock, JF; Waters, MJ; Yoshizato, H; Barclay, JL; Brooks, AJ; Behncken, SN; Kerr, LM; Millard, K; Palethorpe, K; Nielsen, K; , 

2008 

1 

Nature Cell Biology
ISSN: 1465-7392
EISSN: 1476-4679 

NATURE PUBLISHING GROUP 

LONDON 

740-747 

18488018 

10.1038/ncb1737 

WOS:000256350100021 

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 homdimer, with signal transduction by ligand- induced realignment of receptor subunits(1). Based on the crystal structures(2,3), 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.