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.

Základní údaje

Originální název

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

Autoři

CSUKASI, F. (840 Spojené státy), I. DURAN (840 Spojené státy), M. BARAD (840 Spojené státy), Tomáš BÁRTA (203 Česká republika, domácí), Iva GUDERNOVÁ (203 Česká republika, domácí), Lukáš TRANTÍREK (203 Česká republika, domácí), J.H. MARTIN (840 Spojené státy), C.Y. KUO (840 Spojené státy), J. WOODS (840 Spojené státy), H. LEE (840 Spojené státy), D.H. COHN (840 Spojené státy), Pavel KREJČÍ (203 Česká republika, domácí) a D. KRAKOW (840 Spojené státy, garant)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10601 Cell biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 17.200

Kód RIV

RIV/00216224:14110/18:00101652

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000444967400005

Klíčová slova anglicky

mTOR

Štítky

14110513, 14110517, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 12. 3. 2019 16:30, Mgr. Pavla Foltynová, Ph.D.

Anotace

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.

Návaznosti

GA17-09525S, projekt VaV

Název: Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

Investor: Grantová agentura ČR, Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

NV15-33232A, projekt VaV

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

NV15-34405A, projekt VaV

Název: 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 a 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, roč. 10, č. 459, s. 1-11. ISSN 1946-6234. Dostupné z: 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 a 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, roč.~10, č.~459, s.~1-11. ISSN~1946-6234. Dostupné z: https://dx.doi.org/10.1126/scitranslmed.aat9356.

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