CSUKASI, F., I. DURAN, M. BARAD, Tomáš BÁRTA, Iva GUDERNOVÁ, Lukáš TRANTÍREK, J.H. MARTIN, C.Y. KUO, J. WOODS, H. LEE, D.H. COHN, Pavel KREJČÍ and D. KRAKOW. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. Science Translational Medicine. Washington: American Association for the Advancement of Science, 2018, vol. 10, No 459, p. 1-11. ISSN 1946-6234. Available from: https://dx.doi.org/10.1126/scitranslmed.aat9356. |
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@article{1490193, author = {Csukasi, F. and Duran, I. and Barad, M. and Bárta, Tomáš and Gudernová, Iva and Trantírek, Lukáš and Martin, J.H. and Kuo, C.Y. and Woods, J. and Lee, H. and Cohn, D.H. and Krejčí, Pavel and Krakow, D.}, article_location = {Washington}, article_number = {459}, doi = {http://dx.doi.org/10.1126/scitranslmed.aat9356}, keywords = {mTOR}, language = {eng}, issn = {1946-6234}, journal = {Science Translational Medicine}, title = {The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling}, volume = {10}, year = {2018} }
TY - JOUR ID - 1490193 AU - Csukasi, F. - Duran, I. - Barad, M. - Bárta, Tomáš - Gudernová, Iva - Trantírek, Lukáš - Martin, J.H. - Kuo, C.Y. - Woods, J. - Lee, H. - Cohn, D.H. - Krejčí, Pavel - Krakow, D. PY - 2018 TI - The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling JF - Science Translational Medicine VL - 10 IS - 459 SP - 1-11 EP - 1-11 PB - American Association for the Advancement of Science SN - 19466234 KW - mTOR N2 - Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis. ER -
CSUKASI, F., I. DURAN, M. BARAD, Tomáš BÁRTA, Iva GUDERNOVÁ, Lukáš TRANTÍREK, J.H. MARTIN, C.Y. KUO, J. WOODS, H. LEE, D.H. COHN, Pavel KREJČÍ and D. KRAKOW. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. \textit{Science Translational Medicine}. Washington: American Association for the Advancement of Science, 2018, vol.~10, No~459, p.~1-11. ISSN~1946-6234. Available from: https://dx.doi.org/10.1126/scitranslmed.aat9356.
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