A novel dysfunctional growth hormone variant (Ile179Met) exhibits a decreased ability to activate the extracellular signal-regulated kinase pathway.
The pituitary-expressed GH1 gene was screened for mutation in a group of 74 children with familial short stature. Two novel mutations were identified: an Ile179Met substitution and a -360A-->G promoter variant. The Ile179Met variant was shown to exhibit a similar degree of resistance to proteolysis as wild-type GH, indicating that the introduction of Met does not cause significant misfolding. Secretion of Ile179Met GH from rat pituitary cells was also similar to that of wild type. Although receptor binding studies failed to show any difference in binding characteristics, molecular modeling studies suggested that the Ile179Met substitution might nevertheless perturb interactions between GH and the GH receptor loop containing the hotspot residue Trp169, thereby affecting signal transduction. The ability of the Ile179Met variant to activate a signal transducer and activator of transcription (STAT) 5-responsive luciferase reporter gene and induce phosphorylation of STAT 5 and ERK was therefore studied. In contrast to its ability to activate STAT 5 normally, activation of ERK by the Ile179Met variant was reduced to half that observed with wild type. Although differential effects on the activation of distinct signaling pathways by a mutant receptor agonist are unprecedented, these findings also suggest that the ERK pathway could play a role in mediating the action of GH.
Section of Endocrinology, Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom. lewismd@cardiff.ac.uk
Mark D
MD
Lewis
Martin
M
Horan
David S
DS
Millar
Vicky
V
Newsway
Tammy E
TE
Easter
Linda
L
Fryklund
John W
JW
Gregory
Martin
M
Norin
Cristóbal-Jorge
CJ
Del Valle
Juan Pedro
JP
López-Siguero
Ramón
R
Cañete
Luis Fernando
LF
López-Canti
Nieves
N
Díaz-Torrado
Rafael
R
Espino
Angels
A
Ulied
Maurice F
MF
Scanlon
Annie M
AM
Procter
David N
DN
Cooper
D001827:Body Height / Q000235:genetics*; D002648:Child; D018360:Crystallography, X-Ray; D005820:Genetic Testing; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D019382:Human Growth Hormone / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary
D019382:Human Growth Hormone; D020928:Mitogen-Activated Protein Kinases