Publication details

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

Authors

CSUKASI F. DURAN I. BARAD M. BÁRTA Tomáš GUDERNOVÁ Iva TRANTÍREK Lukáš MARTIN J.H. KUO C.Y. WOODS J. LEE H. COHN D.H. KREJČÍ Pavel KRAKOW D.

Year of publication 2018
Type Article in Periodical
Magazine / Source Science Translational Medicine
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1126/scitranslmed.aat9356
Keywords mTOR
Description 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.
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