Detailed Information on Publication Record
2018
The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
CSUKASI, F., I. DURAN, M. BARAD, Tomáš BÁRTA, Iva GUDERNOVÁ et. al.Basic information
Original name
The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
Authors
CSUKASI, F. (840 United States of America), I. DURAN (840 United States of America), M. BARAD (840 United States of America), Tomáš BÁRTA (203 Czech Republic, belonging to the institution), Iva GUDERNOVÁ (203 Czech Republic, belonging to the institution), Lukáš TRANTÍREK (203 Czech Republic, belonging to the institution), J.H. MARTIN (840 United States of America), C.Y. KUO (840 United States of America), J. WOODS (840 United States of America), H. LEE (840 United States of America), D.H. COHN (840 United States of America), Pavel KREJČÍ (203 Czech Republic, belonging to the institution) and D. KRAKOW (840 United States of America, guarantor)
Edition
Science Translational Medicine, Washington, American Association for the Advancement of Science, 2018, 1946-6234
Other information
Language
English
Type of outcome
Článek v odborném periodiku
Field of Study
10601 Cell biology
Country of publisher
United States of America
Confidentiality degree
není předmětem státního či obchodního tajemství
Impact factor
Impact factor: 17.200
RIV identification code
RIV/00216224:14110/18:00101652
Organization unit
Faculty of Medicine
UT WoS
000444967400005
Keywords in English
mTOR
Tags
International impact, Reviewed
Změněno: 12/3/2019 16:30, Mgr. Pavla Foltynová, Ph.D.
Abstract
V originále
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.
Links
GA17-09525S, research and development project |
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NV15-33232A, research and development project |
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NV15-34405A, research and development project |
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