RT Journal Article
T1 The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
A1 Csukasi, Fabiana
A1 Duran, Ivan
A1 Barad, Maya
A1 Barta, Tomas
A1 Gudernova, Iva
A1 Trantirek, Lukas
A1 Martin, Jorge H
A1 Kuo, Caroline Y
A1 Woods, Jeremy
A1 Lee, Hane
A1 Cohn, Daniel H
A1 Krejci, Pavel
A1 Krakow, Deborah
K1 Displasia ósea
AB 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
PB American Association for the Advancement of Science
YR 2018
FD 2018-09-19
LK https://hdl.handle.net/10630/37330
UL https://hdl.handle.net/10630/37330
LA eng
NO Fabiana Csukasi et al. ,The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling.Sci. Transl. Med.10,eaat9356(2018).DOI:10.1126/scitranslmed.aat9356
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 21 ene 2026