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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
Science Translational Medicine, Volume 10, No. 459, Article eaat9356, Year 2018
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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. Copyright © 2018 The Authors, some rights reserved.
Authors & Co-Authors
Barta, Tomas
Czech Republic, Brno
Masaryk University
Kuo, Caroline Y.
United States, Los Angeles
University of California, Los Angeles
Lee, Hane
United States, Los Angeles
University of California, Los Angeles
Cohn, Daniel H.
United States, Los Angeles
University of California, Los Angeles
Krakow, Deborah E.
United States, Los Angeles
University of California, Los Angeles
Statistics
Citations: 33
Authors: 5
Affiliations: 5
Identifiers
Doi:
10.1126/scitranslmed.aat9356
ISSN:
19466234
Research Areas
Cancer