|
Originally published In Press as doi:10.1074/jbc.M300805200 on March 30, 2003
J. Biol. Chem., Vol. 278, Issue 24, 21960-21971, June 13, 2003
Regulation of the Phosphatidylinositol 3-Kinase, Akt/Protein Kinase B, FRAP/Mammalian Target of Rapamycin, and Ribosomal S6 Kinase 1 Signaling Pathways by Thyroid-stimulating Hormone (TSH) and Stimulating type TSH Receptor Antibodies in the Thyroid Gland*
Jae Mi Suh,
Jung Hun Song,
Dong Wook Kim,
Ho Kim,
Hyo Kyun Chung,
Jung Hwan Hwang,
Jin Man Kim  ,
Eun Suk Hwang,
Jongkyeong Chung  ,
Jeung-Hwan Han ¶,
Bo Youn Cho ||,
Heung Kyu Ro and
Minho Shong **
From the
Laboratory of Endocrine Cell Biology, Department of Internal Medicine and the Department of Pathology, Chungnam National University, Taejon 301-721, the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, the ¶Department of Biochemistry, College of Pharmacy, Sungkyunkwan University, Suwon 440-756, and the ||Department of Internal Medicine, Seoul National University, Seoul 110-744, Korea
Thyroid-stimulating hormone (TSH) regulates the growth and differentiation of thyrocytes by activating the TSH receptor (TSHR). This study investigated the roles of the phosphatidylinositol 3-kinase (PI3K), PDK1, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 (S6K1) signaling mechanism by which TSH and the stimulating type TSHR antibodies regulate thyrocyte proliferation and the follicle activities in vitro and in vivo. The TSHR immunoprecipitates exhibited PI3K activity, which was higher in the cells treated with either TSH or 8-bromo-cAMP. TSH and cAMP increased the tyrosine phosphorylation of TSHR and the association between TSHR and the p85 regulatory subunit of PI3K. TSH induced a redistribution of PDK1 from the cytoplasm to the plasma membrane in the cells in a PI3K- and protein kinase A-dependent manner. TSH induced the PDK1-dependent phosphorylation of S6K1 but did not induce Akt/protein kinase B phosphorylation. The TSH-induced S6K1 phosphorylation was inhibited by a dominant negative p85 regulatory subunit or by the PI3K inhibitors wortmannin and LY294002. Rapamycin inhibited the phosphorylation of S6K1 in the cells treated with either TSH or 8-bromo-cAMP. The stimulating type TSHR antibodies from patients with Graves disease also induced S6K1 activation, whereas the blocking type TSHR antibodies from patients with primary myxedema inhibited TSH- but not the insulin-induced phosphorylation of S6K1. In addition, rapamycin treatment in vivo inhibited the TSH-stimulated thyroid follicle hyperplasia and follicle activity. These findings suggest an interaction between TSHR and PI3K, which is stimulated by TSH and cAMP and might involve the downstream S6K1 but not Akt/protein kinase B. This pathway may play a role in the TSH/stimulating type TSH receptor antibody-mediated thyrocyte proliferation in vitro and in the response to TSH in vivo.
Received for publication, January 24, 2003
, and in revised form, March 26, 2003.
* This work was supported by National Research Laboratory Program Grant M1-0104-00-0014 and KOSEF Research Grant 2000-2-20500-007-3 from the Ministry of Science and Technology, Korea. 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.
** To whom correspondence should be addressed: Laboratory of Endocrine Cell Biology, Dept. of Internal Medicine, Chungnam National University School of Medicine, 640 Daesadong Chungku, Taejon 301-040, Korea. Tel.: 82-42-220-7161; Fax: 82-42-257-5753; E-mail: minhos{at}cnu.ac.kr.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. A. Morshed, R. Latif, and T. F. Davies
Characterization of Thyrotropin Receptor Antibody-Induced Signaling Cascades
Endocrinology,
January 1, 2009;
150(1):
519 - 529.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tsui, V. Naik, N. Hoa, C. J. Hwang, N. F. Afifiyan, A. Sinha Hikim, A. G. Gianoukakis, R. S. Douglas, and T. J. Smith
Evidence for an Association between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors: A Tale of Two Antigens Implicated in Graves' Disease
J. Immunol.,
September 15, 2008;
181(6):
4397 - 4405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Fukushima, T. Nedachi, H. Akizawa, M. Akahori, F. Hakuno, and S.-I. Takahashi
Distinct Modes of Activation of Phosphatidylinositol 3-Kinase in Response to Cyclic Adenosine 3', 5'-Monophosphate or Insulin-Like Growth Factor I Play Different Roles in Regulation of Cyclin D1 and p27Kip1 in FRTL-5 Cells
Endocrinology,
July 1, 2008;
149(7):
3729 - 3742.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Yang, C. Yang, A. Farberman, T. C. Rideout, C. F. M. de Lange, J. France, and M. Z. Fan
The mammalian target of rapamycin-signaling pathway in regulating metabolism and growth
J Anim Sci,
April 1, 2008;
86(14_suppl):
E36 - E50.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Marzec, X. Liu, M. Kasprzycka, A. Witkiewicz, P. N. Raghunath, M. El-Salem, E. Robertson, N. Odum, and M. A. Wasik
IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes
Blood,
February 15, 2008;
111(4):
2181 - 2189.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. D. Bassett, A. J. Williams, E. Murphy, A. Boyde, P. G. T. Howell, R. Swinhoe, M. Archanco, F. Flamant, J. Samarut, S. Costagliola, et al.
A Lack of Thyroid Hormones Rather than Excess Thyrotropin Causes Abnormal Skeletal Development in Hypothyroidism
Mol. Endocrinol.,
February 1, 2008;
22(2):
501 - 512.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Brewer, N. Yeager, and A. Di Cristofano
Thyroid-Stimulating Hormone Initiated Proliferative Signals Converge In vivo on the mTOR Kinase without Activating AKT
Cancer Res.,
September 1, 2007;
67(17):
8002 - 8006.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Shinohara, Y. J. Chung, M. Saji, and M. D. Ringel
AKT in Thyroid Tumorigenesis and Progression
Endocrinology,
March 1, 2007;
148(3):
942 - 947.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Yeager, A. Klein-Szanto, S. Kimura, and A. Di Cristofano
Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis
Cancer Res.,
February 1, 2007;
67(3):
959 - 966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Blaser, S. Maschauer, T. Kuwert, and O. Prante
In Vitro Studies on the Signal Transduction of Thyroidal Uptake of 18F-FDG and 131I-Iodide
J. Nucl. Med.,
August 1, 2006;
47(8):
1382 - 1388.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Garcia-Jimenez, M. A. Zaballos, and P. Santisteban
DARPP-32 (Dopamine and 3',5'-Cyclic Adenosine Monophosphate-Regulated Neuronal Phosphoprotein) Is Essential for the Maintenance of Thyroid Differentiation
Mol. Endocrinol.,
December 1, 2005;
19(12):
3060 - 3072.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Wlodarski, M. Kasprzycka, X. Liu, M. Marzec, E. S. Robertson, A. Slupianek, and M. A. Wasik
Activation of Mammalian Target of Rapamycin in Transformed B Lymphocytes Is Nutrient Dependent but Independent of Akt, Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase, Insulin Growth Factor-I, and Serum
Cancer Res.,
September 1, 2005;
65(17):
7800 - 7808.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Braga-Basaria, E. Hardy, R. Gottfried, K. D. Burman, M. Saji, and M. D. Ringel
17-Allylamino-17-Demethoxygeldanamycin Activity against Thyroid Cancer Cell Lines Correlates with Heat Shock Protein 90 Levels
J. Clin. Endocrinol. Metab.,
June 1, 2004;
89(6):
2982 - 2988.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Porcellini, S. Messina, G. De Gregorio, A. Feliciello, A. Carlucci, M. Barone, A. Picascia, A. De Blasi, and E. V. Avvedimento
The Expression of the Thyroid-stimulating Hormone (TSH) Receptor and the cAMP-dependent Protein Kinase RII {beta} Regulatory Subunit Confers TSH-cAMP-dependent Growth to Mouse Fibroblasts
J. Biol. Chem.,
October 17, 2003;
278(42):
40621 - 40630.
[Abstract]
[Full Text]
[PDF]
|
|
|
Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
|
Advertisement
Advertisement
|
