Letter abstract
Nature Cell Biology 10, 740 - 747 (2008)
Published online: 18 May 2008 | doi:10.1038/ncb1737
There is an Erratum (July 2008) associated with this Article.
An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway
Scott W. Rowlinson1,2, Hideo Yoshizato1,3, Johanna L. Barclay1, Andrew J. Brooks1, Stuart N. Behncken1, Linda M. Kerr1, Kirstin Millard1, Kathryn Palethorpe1, Katherine Nielsen1, Jodie Clyde-Smith1, John F. Hancock1 & Michael J. Waters1
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 subunits1. Based on the crystal structures2, 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
, 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.
- Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, St Lucia 4072, Australia.
- Current address: Eli Lilly and Company, Lilly Corporate Center, Drop Code 0444, Indianapolis, Indiana, 46285, USA.
- Current address: Department of Materials Science and Engineering, Nagoya Institue of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan.
Correspondence to: Michael J. Waters1 e-mail: m.waters@imb.uq.edu.au
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Model for growth hormone receptor activation based on subunit rotation within a receptor dimerNature Structural & Molecular Biology Article (01 Sep 2005)
Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormoneNature Letters to Editor (06 Nov 1997)
Ternary complex between placental lactogen and the extracellular domain of the prolactin receptorNature Structural Biology Article (01 Sep 2000)
Linkage of the ubiquitin-conjugating system and the endocytic pathway in ligand-induced internalization of the growth hormone receptorThe EMBO Journal Article (15 Aug 1997)
See all 9 matches for Research
