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

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 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 insulininduced 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.The pituitary glycoprotein hormones ACTH, follicle-stimulating hormone, luteinizing hormone, and TSH 1 control the function of specific target cells in the adrenal gland, gonads, and thyroid. All of these hormones are not only important for hormone production but also for maintaining the glandular weight in their target gland. These hormones bind to ligandspecific cell-surface G-protein-coupled receptors and activate adenylyl cyclase to produce cAMP. These glycoprotein hormone receptors also activate the PI3K-dependent signaling pathways (1). However, it is still unclear how these glycoprotein hormone receptors are coupled to the PI3K signaling pathways.The TSH receptor (TSHR) has many important functions that regulate growth, proliferation, differentiation, and the survival of thyrocytes and increasing hormone production in the thyroid gland (2, 3). TSHR mediates these activities by activating the diverse signaling pathways including the PI3K pathway. The signaling components downstream of TSHR (G␤␥, cAMP, and PKA) may overlap with the downstream components of the PI3K signaling pathway. The G␤␥ subunit of heterotrimeric G-proteins specifically activates PI3K...

FSH-stimulated PTEN activity accounts for the lack of FSH mitogenic effect in prepubertal rat Sertoli cells

“…Differences in cell culture conditions could be amenable for this discrepancy, which otherwise remains obscure. However, it is clearly reminiscent of the observation that TSH, a glycoprotein hormone structurally related to FSH, stimulates p70S6K1 in a PI3K-dependent manner, without activating Akt (Suh et al, 2003). Furthermore, the muscarinic M3 receptor mediates p70S6K1 activation and enhances its phosphorylation on the T389 residue through an mTOR-dependent mechanism, in an astrocytoma cell line.…”

Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway

“…Accordingly, Aktmediated TCS phosphorylation is not critical for mTOR activity during Drosophila development (Dong and Pan, 2004). Furthermore, at least two different ligands -TSH acting on thyroid epithelial cells (Suh et al, 2003) and prostaglandin F2a in luteal cells (Arvisais et al, 2006) can activate mTOR without exerting any appreciable effect on Akt. Finally, in transformed B lymphocytes mTOR activation is mostly, if not completely, PI3K/ Akt-independent .…”

Activation of mTORC1 Signaling Pathway in AIDS-Related Lymphomas

“…They include the CD40 ligand, 28 thyroid-stimulating hormone, 29 fibroblast growth factor-9, 30 polycystein-1, 31 and prostaglandin F2a. 32 In regard to malignant lymphocytes, we found that in anaplastic T/null-cell lymphomas that expresses a chimeric, constitutively activated form of the anaplastic lymphoma kinase, the kinase induces mTORC1 activation.…”