RNF43 inhibits WNT5A-driven signaling and suppresses melanoma
invasion and resistance to the targeted therapy

J 2021

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy

RADASZKIEWICZ, Tomasz Witold, Michaela NOSKOVÁ, Kristína GÖMÖRYOVÁ, Olga VONDÁLOVÁ BLANÁŘOVÁ, Katarzyna Anna RADASZKIEWICZ et. al.

Basic information

Original name

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy

Authors

RADASZKIEWICZ, Tomasz Witold (616 Poland, belonging to the institution), Michaela NOSKOVÁ (203 Czech Republic, belonging to the institution), Kristína GÖMÖRYOVÁ (703 Slovakia, belonging to the institution), Olga VONDÁLOVÁ BLANÁŘOVÁ (203 Czech Republic, belonging to the institution), Katarzyna Anna RADASZKIEWICZ (616 Poland, belonging to the institution), Markéta PÍCKOVÁ (203 Czech Republic, belonging to the institution), Ráchel VÍCHOVÁ, Tomáš GYBEĽ (703 Slovakia, belonging to the institution), Karol KAISER (703 Slovakia, belonging to the institution), Lucia DEMKOVÁ, Lucia KUČEROVÁ, Tomáš BÁRTA (203 Czech Republic, belonging to the institution), David POTĚŠIL (203 Czech Republic, belonging to the institution), Zbyněk ZDRÁHAL (203 Czech Republic, belonging to the institution), Karel SOUČEK (203 Czech Republic, belonging to the institution) and Vítězslav BRYJA (203 Czech Republic, guarantor, belonging to the institution)

Edition

eLife, eLife Sciences Publications Ltd, 2021, 2050-084X

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 8.713

RIV identification code

RIV/00216224:14310/21:00119379

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.7554/eLife.65759

UT WoS

000712036700001

Keywords in English

RNF43; WNT5A; melanoma; ROR1; VANGL1; BRAF V600E; Human; Mouse

Abstract

V originále

RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/beta-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.

Links

GX19-28347X, research and development project

Name: Molekulární a funkční analýza biologie kasein kinázy 1

Investor: Czech Science Foundation

LM2018127, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii (Acronym: CIISB)

Investor: Ministry of Education, Youth and Sports of the CR

LM2018140, research and development project

Name: e-Infrastruktura CZ (Acronym: e-INFRA CZ)

Investor: Ministry of Education, Youth and Sports of the CR

90127, large research infrastructures

Name: CIISB II

Citovat

RADASZKIEWICZ, Tomasz Witold, Michaela NOSKOVÁ, Kristína GÖMÖRYOVÁ, Olga VONDÁLOVÁ BLANÁŘOVÁ, Katarzyna Anna RADASZKIEWICZ, Markéta PÍCKOVÁ, Ráchel VÍCHOVÁ, Tomáš GYBEĽ, Karol KAISER, Lucia DEMKOVÁ, Lucia KUČEROVÁ, Tomáš BÁRTA, David POTĚŠIL, Zbyněk ZDRÁHAL, Karel SOUČEK and Vítězslav BRYJA. RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy. eLife. eLife Sciences Publications Ltd, 2021, vol. 10, October, p. "e65759", 41 pp. ISSN 2050-084X. Available from: https://dx.doi.org/10.7554/eLife.65759.

@article{1806140,
   author = {Radaszkiewicz, Tomasz Witold and Nosková, Michaela and Gömöryová, Kristína and Vondálová Blanářová, Olga and Radaszkiewicz, Katarzyna Anna and Pícková, Markéta and Víchová, Ráchel and Gybeľ, Tomáš and Kaiser, Karol and Demková, Lucia and Kučerová, Lucia and Bárta, Tomáš and Potěšil, David and Zdráhal, Zbyněk and Souček, Karel and Bryja, Vítězslav},
   article_number = {October},
   doi = {http://dx.doi.org/10.7554/eLife.65759},
   keywords = {RNF43; WNT5A; melanoma; ROR1; VANGL1; BRAF V600E; Human; Mouse},
   language = {eng},
   issn = {2050-084X},
   journal = {eLife},
   title = {RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy},
   url = {https://elifesciences.org/articles/65759#info},
   volume = {10},
   year = {2021}
}

TY  - JOUR
ID  - 1806140
AU  - Radaszkiewicz, Tomasz Witold - Nosková, Michaela - Gömöryová, Kristína - Vondálová Blanářová, Olga - Radaszkiewicz, Katarzyna Anna - Pícková, Markéta - Víchová, Ráchel - Gybeľ, Tomáš - Kaiser, Karol - Demková, Lucia - Kučerová, Lucia - Bárta, Tomáš - Potěšil, David - Zdráhal, Zbyněk - Souček, Karel - Bryja, Vítězslav
PY  - 2021
TI  - RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy
JF  - eLife
VL  - 10
IS  - October
SP  - "e65759"
EP  - "e65759"
PB  - eLife Sciences Publications Ltd
SN  - 2050084X
KW  - RNF43
KW  - WNT5A
KW  - melanoma
KW  - ROR1
KW  - VANGL1
KW  - BRAF V600E
KW  - Human
KW  - Mouse
UR  - https://elifesciences.org/articles/65759#info
N2  - RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/beta-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.
ER  -

RADASZKIEWICZ, Tomasz Witold, Michaela NOSKOVÁ, Kristína GÖMÖRYOVÁ, Olga VONDÁLOVÁ BLANÁŘOVÁ, Katarzyna Anna RADASZKIEWICZ, Markéta PÍCKOVÁ, Ráchel VÍCHOVÁ, Tomáš GYBEĽ, Karol KAISER, Lucia DEMKOVÁ, Lucia KUČEROVÁ, Tomáš BÁRTA, David POTĚŠIL, Zbyněk ZDRÁHAL, Karel SOUČEK and Vítězslav BRYJA. RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy. \textit{eLife}. eLife Sciences Publications Ltd, 2021, vol.~10, October, p.~''e65759'', 41 pp. ISSN~2050-084X. Available from: https://dx.doi.org/10.7554/eLife.65759.

Detailed Information on Publication Record