| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
Address all correspondence and requests for reprints to: Ger J. Strous, Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, Room G02.525, 3584 CX Utrecht, The Netherlands. E-mail: strous{at}med.uu.nl.
GH binding to cell surface-localized GH receptors (GHRs) induces a conformational change of the dimerized receptors, resulting in activation of Janus kinase 2 and downstream signaling pathways. Interactions between the extracellular subdomain 2 of adjacent GHR polypeptides result in a 500-Å2 contact interface, which has previously been suggested to stabilize the GH-(GHR)2 complex. In this study, we investigated further the role of subdomain 2 in GHR function. Amino acids that participate in (e.g. aspartic acid 152, tyrosine 200, or serine 201) or lie close to (e.g. asparagine 143 or cysteine 241) the contact interface were mutated in rabbit GHR. Surprisingly, none of the mutations affected GHR dimerization, as demonstrated by coimmunoprecipitation of a truncated, epitope-tagged GHR. However, signal transduction of GHR(D152H), GHR(Y200D), and GHR(S201K) mutants was precluded. More insight into the molecular mechanism of the signaling defect was obtained when we examined the effect of the mutations on the integrity of the GH-(GHR)2 complex in a protease-protection assay. In contrast to wild-type GHR, GHR(N143K), and GHR(C241S), the GHR(D152H), GHR(Y200D), and GHR(S201K) mutants were not protected against protease digestion by GH, indicating that a structural change is prevented. Together, we provide new evidence for a critical role of aspartic acid 152, tyrosine 200, and serine 201 of the GHR contact interface in the GH-induced conformational change to a signaling-competent complex rather than in GHR dimerization.
This article has been cited by other articles:
 |
|
 |
|
  G. Kenth, J. A M. Mergelas, and C. G. Goodyer Developmental changes in the human GH receptor and its signal transduction pathways J. Endocrinol., July 1, 2008; 198(1): 71 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Fang, R. Girgis, B. M. Little, K. L. Pratt, J. Guevara-Aguirre, V. Hwa, and R. G. Rosenfeld Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor-I Deficiency in Inuit Subjects and an Ecuadorian Cohort: Functional Studies of Two Codon 180 GH Receptor Gene Mutations J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 1030 - 1037. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Gates Goodyer, Z. Rhani, and H. Zheng Expression of the Hepatic Specific V1 Messenger Ribonucleic Acid of the Human Growth Hormone Receptor Gene Is Regulated by Hepatic Nuclear Factor (HNF)-4{alpha}2 and HNF-4{alpha}8 Mol. Endocrinol., February 1, 2008; 22(2): 485 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. van den Eijnden and G. J. Strous Autocrine Growth Hormone: Effects on Growth Hormone Receptor Trafficking and Signaling Mol. Endocrinol., November 1, 2007; 21(11): 2832 - 2846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Petkovic, A. Besson, M. Thevis, D. Lochmatter, A. Eble, C. E. Fluck, and P. E. Mullis Evaluation of the Biological Activity of a Growth Hormone (GH) Mutant (R77C) and Its Impact on GH Responsiveness and Stature J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2893 - 2901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yang, X. Wang, J. Jiang, and S. J. Frank Role of the Growth Hormone (GH) Receptor Transmembrane Domain in Receptor Predimerization and GH-Induced Activation Mol. Endocrinol., July 1, 2007; 21(7): 1642 - 1655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Quadt-Akabayov, J. H. Chill, R. Levy, N. Kessler, and J. Anglister Determination of the human type I interferon receptor binding site on human interferon-{alpha}2 by cross saturation and an NMR-based model of the complex Protein Sci., November 1, 2006; 15(11): 2656 - 2668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. M. van den Eijnden, L. L. Lahaye, and G. J. Strous Disulfide bonds determine growth hormone receptor folding, dimerisation and ligand binding J. Cell Sci., August 1, 2006; 119(15): 3078 - 3086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. L. Jorge, F. G. Marchisotti, L. R. Montenegro, L. R. Carvalho, B. B. Mendonca, and I. J. P. Arnhold Growth Hormone (GH) Pharmacogenetics: Influence of GH Receptor Exon 3 Retention or Deletion on First-Year Growth Response and Final Height in Patients with Severe GH Deficiency J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1076 - 1080. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gavutis, S. Lata, P. Lamken, P. Muller, and J. Piehler Lateral Ligand-Receptor Interactions on Membranes Probed by Simultaneous Fluorescence-Interference Detection Biophys. J., June 1, 2005; 88(6): 4289 - 4302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J G Miquet, A I Sotelo, A Bartke, and D Turyn Increased SH2-B{beta} content and membrane association in transgenic mice overexpressing GH J. Endocrinol., May 1, 2005; 185(2): 301 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ahr, M. Denizot, V. Robert-Hebmann, A. Brelot, and M. Biard-Piechaczyk Identification of the Cytoplasmic Domains of CXCR4 Involved in Jak2 and STAT3 Phosphorylation J. Biol. Chem., February 25, 2005; 280(8): 6692 - 6700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Sun, Z. Zheng, P. Tummala, J. Oh, F. Schaefer, and R. Rabkin Chronic Uremia Attenuates Growth Hormone-Induced Signal Transduction in Skeletal Muscle J. Am. Soc. Nephrol., October 1, 2004; 15(10): 2630 - 2636. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
