|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 280, Issue 45, 37471-37480, November 11, 2005
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Role of the Cytokine-induced SH2 Domain-containing Protein CIS in Growth Hormone Receptor Internalization*
From the Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts 02215
The cytokine-inducible SH2 domain-containing protein CIS inhibits signaling from the growth hormone (GH) receptor (GHR) to STAT5b by a proteasome-dependent mechanism. Here, we used the GH-responsive rat liver cell line CWSV-1 to investigate the role of CIS and the proteasome in GH-induced GHR internalization. Cell-surface GHR localization and internalization were monitored in GH-stimulated cells by confocal immunofluorescence microscopy using an antibody directed against the GHR extracellular domain. In GH naïve cells, GHR was detected in small, randomly distributed granules on the cell surface and in the cytoplasm, with accumulation in the perinuclear area. GH treatment induced a rapid (within 5 min) internalization of GH·GHR complexes, which coincided with the onset of GHR tyrosine phosphorylation and the appearance in the cytosol of distinct granular structures containing internalized GH. GHR signaling to STAT5b continued for 
30–40 min, however, indicating that GHR signaling and deactivation of the GH·GHR complex both proceed from an intracellular compartment. The internalization of GH and GHR was inhibited by CIS-R107K, a dominant-negative SH2 domain mutant of CIS, and by the proteasome inhibitors MG132 and epoxomicin, which prolong GHR signaling to STAT5b. GH pulse-chase studies established that the internalized GH·GHR complexes did not recycle back to the cell surface in significant amounts under these conditions. Given the established specificity of CIS-R107K for blocking the GHR signaling inhibitory actions of CIS, but not those of other SOCS/CIS family members, these findings implicate CIS and the proteasome in the control of GHR internalization following receptor activation and suggest that CIS-dependent receptor internalization is a prerequisite for efficient termination of GHR signaling.
Received for publication, April 15, 2005 , and in revised form, September 2, 2005.
* This work was supported in part by National Institutes of Health Grant DK33765 (to D. J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Biology, Boston University, 5 Cummington St., Boston, MA 02215. Fax: 617-353-7404; E-mail: djw{at}bu.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  J. G Miquet, L. Gonzalez, M. N Matos, C. E Hansen, A. Louis, A. Bartke, D. Turyn, and A. I Sotelo Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation J. Endocrinol., August 1, 2008; 198(2): 317 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Piessevaux, L. De Ceuninck, D. Catteeuw, F. Peelman, and J. Tavernier Elongin B/C Recruitment Regulates Substrate Binding by CIS J. Biol. Chem., August 1, 2008; 283(31): 21334 - 21346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Uyttendaele, I. Lemmens, A. Verhee, A.-S. De Smet, J. Vandekerckhove, D. Lavens, F. Peelman, and J. Tavernier Mammalian Protein-Protein Interaction Trap (MAPPIT) Analysis of STAT5, CIS, and SOCS2 Interactions with the Growth Hormone Receptor Mol. Endocrinol., November 1, 2007; 21(11): 2821 - 2831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Deng, K. He, X. Wang, N. Yang, C. Thangavel, J. Jiang, S. Y. Fuchs, and S. J. Frank Determinants of Growth Hormone Receptor Down-Regulation Mol. Endocrinol., July 1, 2007; 21(7): 1537 - 1551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Thangavel and B. H. Shapiro A Molecular Basis for the Sexually Dimorphic Response to Growth Hormone Endocrinology, June 1, 2007; 148(6): 2894 - 2903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Reddy, M. J. Pushpanathan, R. F. Ransom, L. B. Holzman, F. C. Brosius III, M. Diakonova, P. Mathieson, M. A. Saleem, E. O. List, J. J. Kopchick, et al. Identification of the Glomerular Podocyte as a Target for Growth Hormone Action Endocrinology, May 1, 2007; 148(5): 2045 - 2055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Piessevaux, D. Lavens, T. Montoye, J. Wauman, D. Catteeuw, J. Vandekerckhove, D. Belsham, F. Peelman, and J. Tavernier Functional Cross-modulation between SOCS Proteins Can Stimulate Cytokine Signaling J. Biol. Chem., November 3, 2006; 281(44): 32953 - 32966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Waxman and C. O'Connor Growth Hormone Regulation of Sex-Dependent Liver Gene Expression Mol. Endocrinol., November 1, 2006; 20(11): 2613 - 2629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lee, J. R. Hutson, V. K.-F. Tzau, and D. S. Riddick Regulation of Constitutive Mouse Hepatic Cytochromes P450 and Growth Hormone Signaling Components by 3-Methylcholanthrene Drug Metab. Dispos., September 1, 2006; 34(9): 1530 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Bullock, J. E. Debreczeni, A. M. Edwards, M. Sundstrom, and S. Knapp Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase PNAS, May 16, 2006; 103(20): 7637 - 7642. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |