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The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling.
- Source :
-
Science translational medicine [Sci Transl Med] 2018 Sep 19; Vol. 10 (459). - Publication Year :
- 2018
-
Abstract
- 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.<br /> (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Subjects :
- Amino Acid Sequence
Growth Plate metabolism
HEK293 Cells
Homozygote
Humans
Inheritance Patterns genetics
Intracellular Signaling Peptides and Proteins metabolism
Mechanistic Target of Rapamycin Complex 1 metabolism
Mechanistic Target of Rapamycin Complex 2 metabolism
Mutant Proteins chemistry
Mutant Proteins metabolism
Mutation, Missense genetics
Protein Kinases chemistry
Protein Kinases deficiency
Protein Kinases genetics
Proteolysis
Osteogenesis
Parathyroid Hormone metabolism
Parathyroid Hormone-Related Protein metabolism
Protein Kinases metabolism
Signal Transduction
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 10
- Issue :
- 459
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30232230
- Full Text :
- https://doi.org/10.1126/scitranslmed.aat9356