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The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

F. Csukasi, I. Duran, M. Barad, T. Barta, I. Gudernova, L. Trantirek, JH. Martin, CY. Kuo, J. Woods, H. Lee, DH. Cohn, P. Krejci, D. Krakow,

. 2018 ; 10 (459) : . [pub] 20180919

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19045236

Grantová podpora
R01 AR066124 NIAMS NIH HHS - United States
R01 AR062651 NIAMS NIH HHS - United States
R01 DE019567 NIDCR NIH HHS - United States
NV15-33232A MZ0 CEP - Centrální evidence projektů
NV15-34405A MZ0 CEP - Centrální evidence projektů

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.

Central European Institute of Technology Masaryk University 62500 Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Department of Histology and Embryology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Department of Orthopaedic Surgery University of California Los Angeles Los Angeles CA 90095 USA

Department of Orthopaedic Surgery University of California Los Angeles Los Angeles CA 90095 USA Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic Institute of Animal Physiology and Genetics of the Czech Academy of Sciences 60200 Brno Czech Republic

Department of Orthopaedic Surgery University of California Los Angeles Los Angeles CA 90095 USA Orthopaedic Institute for Children University of California Los Angeles Los Angeles CA 90095 USA Department of Human Genetics University of California Los Angeles Los Angeles CA 90095 USA Department of Obstetrics and Gynecology University of California Los Angeles Los Angeles CA 90095 USA

Department of Orthopaedic Surgery University of California Los Angeles Los Angeles CA 90095 USA Orthopaedic Institute for Children University of California Los Angeles Los Angeles CA 90095 USA Department of Molecular Cell and Developmental Biology University of California Los Angeles Los Angeles CA 90095 USA

Department of Pathology and Laboratory Medicine University of California Los Angeles Los Angeles CA 90095 USA

Department of Pediatrics University of California Los Angeles Los Angeles CA 90095 USA

Citace poskytuje Crossref.org

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