Huwe1-mediated ubiquitylation of dishevelled defines a negative
feedback loop in the wnt signaling pathway.

J 2014

Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway.

DE GROOT, Reinoud E. A., Sri Ranjani GANJI, Ondřej BERNATÍK, Bethan LLOYD-LEWIS, Katja SEIPEL et. al.

Základní údaje

Originální název

Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway.

Autoři

DE GROOT, Reinoud E. A. (528 Nizozemské království), Sri Ranjani GANJI (356 Indie, domácí), Ondřej BERNATÍK (203 Česká republika, domácí), Bethan LLOYD-LEWIS (826 Velká Británie a Severní Irsko), Katja SEIPEL (826 Velká Británie a Severní Irsko), Kateřina ŠEDOVÁ (203 Česká republika, domácí), Zbyněk ZDRÁHAL (203 Česká republika, domácí), Vishnu M. DHOPLE (276 Německo), Trevor C DALE (826 Velká Británie a Severní Irsko), Hendrik C. KORSWAGEN (528 Nizozemské království) a Vítězslav BRYJA (203 Česká republika, garant, domácí)

Vydání

Science Signaling, 2014, 1937-9145

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

Genetika a molekulární biologie

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.279

Kód RIV

RIV/00216224:14310/14:00073568

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1126/scisignal.2004985

UT WoS

000333557500002

Klíčová slova anglicky

Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway.

Štítky

AKR, rivok

Změněno: 26. 3. 2015 15:59, Ing. Andrea Mikešková

Anotace

V originále

Wnt signaling plays a central role in development, adult tissue homeostasis, and cancer. Several steps in the canonical Wnt/beta-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization, or interactions of target proteins. To identify regulators of the Wnt/beta-catenin pathway, we performed an RNA interference screen in Caenorhabditis elegans and identified the HECT domain-containing ubiquitin ligase EEL-1 as an inhibitor of Wnt signaling. In human embryonic kidney 293T cells, knockdown of the EEL-1 homolog Huwe1 enhanced the activity of a Wnt reporter in cells stimulated with Wnt3a or in cells that overexpressed casein kinase 1 (CK1) or a constitutively active mutant of the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6). However, knockdown of Huwe1 had no effect on reporter gene expression in cells expressing constitutively active beta-catenin, suggesting that Huwe1 inhibited Wnt signaling upstream of beta-catenin and downstream of CK1 and LRP6. Huwe1 bound to and ubiquitylated the cytoplasmic Wnt pathway component Dishevelled (Dvl) in a Wnt3a- and CK1 epsilon-dependent manner. Mass spectrometric analysis showed that Huwe1 promoted K63-linked, but not K48-linked, polyubiquitination of Dvl. Instead of targeting Dvl for degradation, ubiquitylation of the DIX domain of Dvl by Huwe1 inhibited Dvl multimerization, which is necessary for its function. Our findings indicate that Huwe1 is part of an evolutionarily conserved negative feedback loop in the Wnt/beta-catenin pathway.

Návaznosti

CZ.1.05/1.1.00/02.0068, interní kód MU

Název: CEITEC - středoevropský technologický institut (Akronym: CEITEC)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC - středoevropský technologický institut, 1.1 Evropská centra excelence

GA204/09/0498, projekt VaV

Název: Dynamika proteinů interagujících s Dishevelled a jejich význam pro Wnt signálování

Investor: Grantová agentura ČR, Dynamika proteinů interagujících s Dishevelled a jejich význam pro Wnt signálování

GD204/09/H058, projekt VaV

Název: Mezibuněčná signalizace ve vývoji organismu a vzniku onemocnění

Investor: Grantová agentura ČR, Mezibuněčná signalizace ve vývoji organismu a vzniku onemocnění

MSM0021622430, záměr

Název: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Citovat

DE GROOT, Reinoud E. A., Sri Ranjani GANJI, Ondřej BERNATÍK, Bethan LLOYD-LEWIS, Katja SEIPEL, Kateřina ŠEDOVÁ, Zbyněk ZDRÁHAL, Vishnu M. DHOPLE, Trevor C DALE, Hendrik C. KORSWAGEN a Vítězslav BRYJA. Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway. Science Signaling. 2014, roč. 7, č. 317, s. "ra26", 10 s. ISSN 1937-9145. Dostupné z: https://dx.doi.org/10.1126/scisignal.2004985.

@article{1173921,
   author = {de Groot, Reinoud E. A. and Ganji, Sri Ranjani and Bernatík, Ondřej and LloydandLewis, Bethan and Seipel, Katja and Šedová, Kateřina and Zdráhal, Zbyněk and Dhople, Vishnu M. and Dale, Trevor C and Korswagen, Hendrik C. and Bryja, Vítězslav},
   article_number = {317},
   doi = {http://dx.doi.org/10.1126/scisignal.2004985},
   keywords = {Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway.},
   language = {eng},
   issn = {1937-9145},
   journal = {Science Signaling},
   title = {Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway.},
   url = {http://www.ncbi.nlm.nih.gov/pubmed/?term=Huwe1-mediated+ubiquitylation+of+Dvl+defines+a+novel+negative+feedback+loop+in+the+Wnt+signaling+pathway.},
   volume = {7},
   year = {2014}
}

TY  - JOUR
ID  - 1173921
AU  - de Groot, Reinoud E. A. - Ganji, Sri Ranjani - Bernatík, Ondřej - Lloyd-Lewis, Bethan - Seipel, Katja - Šedová, Kateřina - Zdráhal, Zbyněk - Dhople, Vishnu M. - Dale, Trevor C - Korswagen, Hendrik C. - Bryja, Vítězslav
PY  - 2014
TI  - Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway.
JF  - Science Signaling
VL  - 7
IS  - 317
SP  - "ra26"
EP  - "ra26"
SN  - 19379145
KW  - Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway.
UR  - http://www.ncbi.nlm.nih.gov/pubmed/?term=Huwe1-mediated+ubiquitylation+of+Dvl+defines+a+novel+negative+feedback+loop+in+the+Wnt+signaling+pathway.
N2  - Wnt signaling plays a central role in development, adult tissue homeostasis, and cancer. Several steps in the canonical Wnt/beta-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization, or interactions of target proteins. To identify regulators of the Wnt/beta-catenin pathway, we performed an RNA interference screen in Caenorhabditis elegans and identified the HECT domain-containing ubiquitin ligase EEL-1 as an inhibitor of Wnt signaling. In human embryonic kidney 293T cells, knockdown of the EEL-1 homolog Huwe1 enhanced the activity of a Wnt reporter in cells stimulated with Wnt3a or in cells that overexpressed casein kinase 1 (CK1) or a constitutively active mutant of the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6). However, knockdown of Huwe1 had no effect on reporter gene expression in cells expressing constitutively active beta-catenin, suggesting that Huwe1 inhibited Wnt signaling upstream of beta-catenin and downstream of CK1 and LRP6. Huwe1 bound to and ubiquitylated the cytoplasmic Wnt pathway component Dishevelled (Dvl) in a Wnt3a- and CK1 epsilon-dependent manner. Mass spectrometric analysis showed that Huwe1 promoted K63-linked, but not K48-linked, polyubiquitination of Dvl. Instead of targeting Dvl for degradation, ubiquitylation of the DIX domain of Dvl by Huwe1 inhibited Dvl multimerization, which is necessary for its function. Our findings indicate that Huwe1 is part of an evolutionarily conserved negative feedback loop in the Wnt/beta-catenin pathway.
ER  -

DE GROOT, Reinoud E. A., Sri Ranjani GANJI, Ondřej BERNATÍK, Bethan LLOYD-LEWIS, Katja SEIPEL, Kateřina ŠEDOVÁ, Zbyněk ZDRÁHAL, Vishnu M. DHOPLE, Trevor C DALE, Hendrik C. KORSWAGEN a Vítězslav BRYJA. Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the wnt signaling pathway. \textit{Science Signaling}. 2014, roč.~7, č.~317, s.~''ra26'', 10 s. ISSN~1937-9145. Dostupné z: https://dx.doi.org/10.1126/scisignal.2004985.

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