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The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
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SYSNO ASEP 0495758 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling Tvůrce(i) Csukasi, F. (US)
Duran, I. (US)
Barad, M. (US)
Bárta, T. (CZ)
Gudernová, I. (CZ)
Trantírek, L. (CZ)
Martin, J. H. (US)
Kuo, C. Y. (US)
Woods, J. (US)
Lee, H. (US)
Cohn, D. H. (US)
Krejčí, Pavel (UZFG-Y) ORCID
Krakow, D. (US)Číslo článku eaat9356 Zdroj.dok. Science Translational Medicine. - : American Association for the Advancement of Science - ISSN 1946-6234
Roč. 10, č. 459 (2018)Poč.str. 11 s. Forma vydání Tištěná - P Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova terminal differentiation ; skeletal growth ; cell-growth Vědní obor RIV EA - Morfologické obory a cytologie Obor OECD Cell biology Institucionální podpora UZFG-Y - RVO:67985904 UT WOS 000444967400005 EID SCOPUS 85053506118 DOI 10.1126/scitranslmed.aat9356 Anotace 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. Pracoviště Ústav živočišné fyziologie a genetiky Kontakt Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Rok sběru 2019
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