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

J 2018

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

CSUKASI, F., I. DURAN, M. BARAD, Tomáš BÁRTA, Iva GUDERNOVÁ et. al.

Basic information

Original name

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

Authors

CSUKASI, F. (840 United States of America), I. DURAN (840 United States of America), M. BARAD (840 United States of America), Tomáš BÁRTA (203 Czech Republic, belonging to the institution), Iva GUDERNOVÁ (203 Czech Republic, belonging to the institution), Lukáš TRANTÍREK (203 Czech Republic, belonging to the institution), J.H. MARTIN (840 United States of America), C.Y. KUO (840 United States of America), J. WOODS (840 United States of America), H. LEE (840 United States of America), D.H. COHN (840 United States of America), Pavel KREJČÍ (203 Czech Republic, belonging to the institution) and D. KRAKOW (840 United States of America, guarantor)

Edition

Science Translational Medicine, Washington, American Association for the Advancement of Science, 2018, 1946-6234

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 17.200

RIV identification code

RIV/00216224:14110/18:00101652

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1126/scitranslmed.aat9356

UT WoS

000444967400005

Keywords in English

mTOR

Abstract

V originále

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.

Links

GA17-09525S, research and development project

Name: Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

Investor: Czech Science Foundation

NV15-33232A, research and development project

Name: Identifikace nových možností léčby achondroplásie prostřednictvím analýzy interakce FGFR3 a adaptérového proteinu Frs2

NV15-34405A, research and development project

Name: Identifikace nových možností léčby chronické myeloidní leukémie pomocí systematické analýzy interaktomu proteinu BCR-ABL

Citovat

CSUKASI, F., I. DURAN, M. BARAD, Tomáš BÁRTA, Iva GUDERNOVÁ, Lukáš TRANTÍREK, J.H. MARTIN, C.Y. KUO, J. WOODS, H. LEE, D.H. COHN, Pavel KREJČÍ and D. KRAKOW. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. Science Translational Medicine. Washington: American Association for the Advancement of Science, 2018, vol. 10, No 459, p. 1-11. ISSN 1946-6234. Available from: https://dx.doi.org/10.1126/scitranslmed.aat9356.

@article{1490193,
   author = {Csukasi, F. and Duran, I. and Barad, M. and Bárta, Tomáš and Gudernová, Iva and Trantírek, Lukáš and Martin, J.H. and Kuo, C.Y. and Woods, J. and Lee, H. and Cohn, D.H. and Krejčí, Pavel and Krakow, D.},
   article_location = {Washington},
   article_number = {459},
   doi = {http://dx.doi.org/10.1126/scitranslmed.aat9356},
   keywords = {mTOR},
   language = {eng},
   issn = {1946-6234},
   journal = {Science Translational Medicine},
   title = {The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling},
   volume = {10},
   year = {2018}
}

TY  - JOUR
ID  - 1490193
AU  - 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.
PY  - 2018
TI  - The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
JF  - Science Translational Medicine
VL  - 10
IS  - 459
SP  - 1-11
EP  - 1-11
PB  - American Association for the Advancement of Science
SN  - 19466234
KW  - mTOR
N2  - 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.
ER  -

CSUKASI, F., I. DURAN, M. BARAD, Tomáš BÁRTA, Iva GUDERNOVÁ, Lukáš TRANTÍREK, J.H. MARTIN, C.Y. KUO, J. WOODS, H. LEE, D.H. COHN, Pavel KREJČÍ and D. KRAKOW. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. \textit{Science Translational Medicine}. Washington: American Association for the Advancement of Science, 2018, vol.~10, No~459, p.~1-11. ISSN~1946-6234. Available from: https://dx.doi.org/10.1126/scitranslmed.aat9356.

Detailed Information on Publication Record