Thyroid-stimulating hormone initiated proliferative signals converge in vivo on the mTOR kinase without activating AKT.
Thyroid-stimulating hormone (TSH) has long been recognized as the major proliferative and functional stimulus for thyroid follicular cells. TSH receptor (TSHR) engagement stimulates the production of cyclic AMP and the subsequent activation of downstream effector molecules, including protein kinase A, S6K1, and Rap1, whereas the role of the RAS and phosphatidylinositol-3-kinase signaling cascades downstream of TSHR is still controversial. Despite the abundance of candidates, it is still unclear which of these pathways represent(s) the key mitogenic output of TSH-initiated signaling. We have used an in vivo model of goitrogenesis to dissect the contribution of these pathways to TSH-induced thyrocyte proliferation and thyroid hyperplasia. We show that the in vivo proliferative response to chronic TSHR stimulation relies heavily on the activation of the mTOR/S6K1 axis, and that mTOR inhibition during goitrogenic stimulation abrogates the hyperplastic but not the hypertrophic thyrocyte responses to TSH, thus functionally uncoupling these two processes. Strikingly, goitrogenesis was not associated with an increase in AKT phosphorylation levels, underlining the existence of an AKT-independent pathway leading to mTOR activation upon TSH stimulation.
Brewer
Charlene
C
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Yeager
Nicole
N
Di Cristofano
Antonio
A
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D006965:Hyperplasia / Q000139:chemically induced; D051379:Mice; D008815:Mice, Inbred Strains; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D013972:Thyrotropin / Q000009:adverse effects / Q000494:pharmacology*