Roles of individual human Dishevelled paralogs in the Wnt
signalling pathways

J 2021

Roles of individual human Dishevelled paralogs in the Wnt signalling pathways

PACLÍKOVÁ, Petra, Tomasz Witold RADASZKIEWICZ, David POTĚŠIL, Jakub HARNOŠ, Zbyněk ZDRÁHAL et. al.

Základní údaje

Originální název

Roles of individual human Dishevelled paralogs in the Wnt signalling pathways

Autoři

PACLÍKOVÁ, Petra (203 Česká republika, domácí), Tomasz Witold RADASZKIEWICZ (616 Polsko, domácí), David POTĚŠIL (203 Česká republika, domácí), Jakub HARNOŠ (203 Česká republika, domácí), Zbyněk ZDRÁHAL (203 Česká republika, domácí) a Vítězslav BRYJA (203 Česká republika, garant, domácí)

Vydání

Cellular Signalling, Elsevier, 2021, 0898-6568

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.850

Kód RIV

RIV/00216224:14310/21:00124350

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1016/j.cellsig.2021.110058

UT WoS

000685349100004

Klíčová slova anglicky

Dishevelled 1; 2; 3; Wnt signalling; ROR1; Axin1; CRISPR; Cas9

Štítky

CF PROT, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 10. 10. 2024 14:13, Ing. Martina Blahová

Anotace

V originále

Dishevelled (DVL) proteins are key mediators of most Wnt pathways. In all vertebrates, three DVL paralogs are present (DVL1, DVL2 and DVL3) but it is poorly defined to what extent they are functionally redundant. Here, we generated T-REx HEK 293 cells with only one DVL paralog (i.e., DVL1-only, DVL2-only, and DVL3-only) and compared their response to Wnt-3a and Wnt-5a ligands with wild type and DVL triple knockout cells. We show that DVL is essential, in addition to the previously shown Wnt-3a-induced phosphorylation of LRP6 and transcriptional activation of TCF/LEF-dependent reporter, also for Wnt-3a-induced degradation of AXIN1 and Wnt5a-induced phosphorylation of ROR1. We have quantified the molar ratios of DVL1:DVL2:DVL3 in our model to be approximately 4:80:16. Interestingly, DVL-only cells do not compensate for the lack of other paralogs and are still fully functional in all analyzed readouts with the exception of Wnt-3a-induced transcription assessed by TopFlash assay. In this assay, the DVL1-only cell line was the most potent; on the contrary, the DVL3-only cell line exhibited only the negligible capacity to mediate Wnt signals. Using a novel model system - complementation assays in T-REx HEK 293 with amplified Wnt signal response (RNF43/ZNRF3/DVL1/DVL2/DVL3 penta KO cells) we demonstrate that it is not the total amount of DVL but ratio of individual paralogs what decides the signal strength. In sum, this study contributes to our better understanding of the role of individual human DVL paralogs in the Wnt pathway.

Návaznosti

EF16_025/0007381, projekt VaV

Název: Preklinická progrese nových organických sloučenin s cílenou biologickou aktivitou

LM2018127, projekt VaV

Název: Česká infrastruktura pro integrativní strukturní biologii (Akronym: CIISB)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Czech Infrastructure for Integrative Structural Biology

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

PACLÍKOVÁ, Petra, Tomasz Witold RADASZKIEWICZ, David POTĚŠIL, Jakub HARNOŠ, Zbyněk ZDRÁHAL a Vítězslav BRYJA. Roles of individual human Dishevelled paralogs in the Wnt signalling pathways. Cellular Signalling. Elsevier, 2021, roč. 85, September, s. 110058-110068. ISSN 0898-6568. Dostupné z: https://dx.doi.org/10.1016/j.cellsig.2021.110058.

@article{1838561,
   author = {Paclíková, Petra and Radaszkiewicz, Tomasz Witold and Potěšil, David and Harnoš, Jakub and Zdráhal, Zbyněk and Bryja, Vítězslav},
   article_number = {September},
   doi = {http://dx.doi.org/10.1016/j.cellsig.2021.110058},
   keywords = {Dishevelled 1; 2; 3; Wnt signalling; ROR1; Axin1; CRISPR; Cas9},
   language = {eng},
   issn = {0898-6568},
   journal = {Cellular Signalling},
   title = {Roles of individual human Dishevelled paralogs in the Wnt signalling pathways},
   url = {https://www.sciencedirect.com/science/article/pii/S0898656821001479#!},
   volume = {85},
   year = {2021}
}

TY  - JOUR
ID  - 1838561
AU  - Paclíková, Petra - Radaszkiewicz, Tomasz Witold - Potěšil, David - Harnoš, Jakub - Zdráhal, Zbyněk - Bryja, Vítězslav
PY  - 2021
TI  - Roles of individual human Dishevelled paralogs in the Wnt signalling pathways
JF  - Cellular Signalling
VL  - 85
IS  - September
SP  - 110058
EP  - 110058
PB  - Elsevier
SN  - 08986568
KW  - Dishevelled 1
KW  - 2
KW  - 3
KW  - Wnt signalling
KW  - ROR1
KW  - Axin1
KW  - CRISPR
KW  - Cas9
UR  - https://www.sciencedirect.com/science/article/pii/S0898656821001479#!
N2  - Dishevelled (DVL) proteins are key mediators of most Wnt pathways. In all vertebrates, three DVL paralogs are present (DVL1, DVL2 and DVL3) but it is poorly defined to what extent they are functionally redundant. Here, we generated T-REx HEK 293 cells with only one DVL paralog (i.e., DVL1-only, DVL2-only, and DVL3-only) and compared their response to Wnt-3a and Wnt-5a ligands with wild type and DVL triple knockout cells. We show that DVL is essential, in addition to the previously shown Wnt-3a-induced phosphorylation of LRP6 and transcriptional activation of TCF/LEF-dependent reporter, also for Wnt-3a-induced degradation of AXIN1 and Wnt5a-induced phosphorylation of ROR1. We have quantified the molar ratios of DVL1:DVL2:DVL3 in our model to be approximately 4:80:16. Interestingly, DVL-only cells do not compensate for the lack of other paralogs and are still fully functional in all analyzed readouts with the exception of Wnt-3a-induced transcription assessed by TopFlash assay. In this assay, the DVL1-only cell line was the most potent; on the contrary, the DVL3-only cell line exhibited only the negligible capacity to mediate Wnt signals. Using a novel model system - complementation assays in T-REx HEK 293 with amplified Wnt signal response (RNF43/ZNRF3/DVL1/DVL2/DVL3 penta KO cells) we demonstrate that it is not the total amount of DVL but ratio of individual paralogs what decides the signal strength. In sum, this study contributes to our better understanding of the role of individual human DVL paralogs in the Wnt pathway.
ER  -

PACLÍKOVÁ, Petra, Tomasz Witold RADASZKIEWICZ, David POTĚŠIL, Jakub HARNOŠ, Zbyněk ZDRÁHAL a Vítězslav BRYJA. Roles of individual human Dishevelled paralogs in the Wnt signalling pathways. \textit{Cellular Signalling}. Elsevier, 2021, roč.~85, September, s.~110058-110068. ISSN~0898-6568. Dostupné z: https://dx.doi.org/10.1016/j.cellsig.2021.110058.

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