| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 22, 2005
Accepted on February 15, 2006
Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, AL; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL; Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL; Amgen Incorporated, Seattle, WA
* To whom correspondence should be addressed. E-mail: sjfrank{at}uab.edu.
Growth hormone (GH) signals through the GH receptor (GHR), a cytokine receptor superfamily member that couples to the cytoplasmic tyrosine kinase, JAK2. In addition to its role in signaling, we recently implicated JAK2 in regulation of cell surface GHR abundance by modulation of GHR trafficking and mature GHR stability. GHR is a target for constitutive and inducible metalloprotease-mediated cleavage that alters surface GHR levels and can modulate GH signaling. We previously found that metalloprotease cleavage of GHR is dramatically lessened in fibroblasts derived from mice with targeted deletion of the zinc binding domain of TACE (tumor necrosis factor-
cleaving enzyme; ADAM17), implicating this transmembrane ectoenzyme as a GHR metalloprotease. In this study, we used a human fibrosarcoma reconstitution system to compare the effects of RNAi-mediated knockdown of TACE vs. a related metalloprotease, ADAM10. We found that TACE knockdown dramatically reduced both the pace and degree of inducible GHR proteolysis and augmented the abundance of mature GHR, suggesting a role for TACE in constitutive receptor proteolysis in this system as well. Notably, ADAM10 knockdown also reduced inducible GHR proteolysis, although to a lesser degree than TACE knockdown, suggesting a contribution from this metalloprotease also. To determine if JAK2 affects GHR proteolysis, we compared JAK2-deficient vs. JAK2-replete cells and found that PMA-induced GHR proteolysis was significantly diminished in cells that lack JAK2. Reconstitution with a GHR mutant that lacks the Box 1 region (which mediates JAK2 association) resulted in PMA-induced proteolysis similar in degree to that of the wild-type GHR in JAK2-deficient cells. Introduction of JAK2 did not affect proteolysis of this Box 1 deletent GHR, suggesting GHR-JAK2 association is required for JAK2 to affect GHR proteolysis. Additionally, the inhibitory effect of anti-GHRext-mAb, a conformation-sensitive GHR antibody, on receptor proteolysis was lost in cells that lack JAK2. Our data indicate that GHR's susceptibility to proteolysis is substantially affected by JAK2, suggesting yet another role for this kinase in determining GH sensitivity.
This article has been cited by other articles:
 |
|
 |
|
  X. Wang, J. Jiang, J. Warram, G. Baumann, Y. Gan, R. K. Menon, L. A. Denson, K. R. Zinn, and S. J. Frank Endotoxin-Induced Proteolytic Reduction in Hepatic Growth Hormone (GH) Receptor: A Novel Mechanism for GH Insensitivity Mol. Endocrinol., June 1, 2008; 22(6): 1427 - 1437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yang, J. F. Langenheim, X. Wang, J. Jiang, W. Y. Chen, and S. J. Frank Activation of Growth Hormone Receptors by Growth Hormone and Growth Hormone Antagonist Dimers: Insights into Receptor Triggering Mol. Endocrinol., April 1, 2008; 22(4): 978 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Loesch, L. Deng, X. Wang, K. He, J. Jiang, and S. J. Frank Endoplasmic Reticulum-Associated Degradation of Growth Hormone Receptor in Janus Kinase 2-Deficient Cells Endocrinology, December 1, 2007; 148(12): 5955 - 5965. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Asa, R. DiGiovanni, J. Jiang, M. L. Ward, K. Loesch, S. Yamada, T. Sano, K. Yoshimoto, S. J. Frank, and S. Ezzat A Growth Hormone Receptor Mutation Impairs Growth Hormone Autofeedback Signaling in Pituitary Tumors Cancer Res., August 1, 2007; 67(15): 7505 - 7511. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. J. Frank, X. Wang, K. He, N. Yang, P. Fang, R. G. Rosenfeld, V. Hwa, T. R. Chaudhuri, L. Deng, and K. R. Zinn In Vivo Imaging of Hepatic Growth Hormone Signaling Mol. Endocrinol., November 1, 2006; 20(11): 2819 - 2830. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
