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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
- Source :
- Journal of Biological Chemistry. 278:21960-21971
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- 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 p85alpha 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 p85alpha 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.
- Subjects :
- Time Factors
endocrine system diseases
Thyroid Gland
8-Bromo Cyclic Adenosine Monophosphate
Thyrotropin
Biochemistry
Rats, Sprague-Dawley
Wortmannin
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Protein Isoforms
Phosphorylation
Cells, Cultured
Microscopy, Confocal
TOR Serine-Threonine Kinases
Flow Cytometry
Immunohistochemistry
Signal transduction
Cell Division
hormones, hormone substitutes, and hormone antagonists
Protein Binding
Signal Transduction
endocrine system
medicine.medical_specialty
Morpholines
Blotting, Western
P70-S6 Kinase 1
Protein Serine-Threonine Kinases
Biology
Transfection
Models, Biological
Ribosomal Protein S6 Kinases, 90-kDa
Gene Expression Regulation, Enzymologic
Thyroid-stimulating hormone
Proto-Oncogene Proteins
Internal medicine
medicine
Animals
Humans
Protein kinase A
Molecular Biology
Protein kinase B
Sirolimus
Dose-Response Relationship, Drug
Ribosomal Protein S6 Kinases
Tyrosine phosphorylation
Cell Biology
Precipitin Tests
Protein Structure, Tertiary
Rats
Androstadienes
Spectrometry, Fluorescence
Endocrinology
Microscopy, Fluorescence
chemistry
Chromones
Immunoglobulin G
Protein Kinases
Proto-Oncogene Proteins c-akt
Thymidine
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 278
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....994ce16eb802b7e8bbdc6723ce2a8cf6