Metabolic stress regulates ERK activity by controlling KSR-RAF
heterodimerization

J 2018

Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization

VERLANDE, Amandine, Michaela KRAFČÍKOVÁ, David POTĚŠIL, Lukáš TRANTÍREK, Zbyněk ZDRÁHAL et. al.

Basic information

Original name

Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization

Authors

VERLANDE, Amandine (250 France, belonging to the institution), Michaela KRAFČÍKOVÁ (703 Slovakia, belonging to the institution), David POTĚŠIL (203 Czech Republic, belonging to the institution), Lukáš TRANTÍREK (203 Czech Republic, belonging to the institution), Zbyněk ZDRÁHAL (203 Czech Republic, belonging to the institution), M. ELKALAF (203 Czech Republic), J. TRNKA (203 Czech Republic), Karel SOUČEK (203 Czech Republic, belonging to the institution), N. RAUCH (372 Ireland), J. RAUCH (372 Ireland), W. KOLCH (372 Ireland) and Stjepan ULDRIJAN (203 Czech Republic, guarantor, belonging to the institution)

Edition

EMBO reports, Hoboken, Wiley-Blackwell, 2018, 1469-221X

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 8.383

RIV identification code

RIV/00216224:14110/18:00100832

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.15252/embr.201744524

UT WoS

000424166400015

Keywords in English

cell cycle arrest; cell survival; melanoma; metabolic stress; RAF-ERK signaling

Abstract

V originále

Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS-mutant cells, and with oncogenic BRAF in BRAF(V600E)-mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS-mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAF(V600E)-mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary.

Links

GA14-12166S, research and development project

Name: Regulace dráhy nádorového supresoru p53 novými vazebnými partnery onkogenů Mdm2 a Mdm4

Investor: Czech Science Foundation

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

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

MUNI/A/0810/2016, interní kód MU

Name: Molekulární a buněčná biologie

Investor: Masaryk University, Category A

Citovat

VERLANDE, Amandine, Michaela KRAFČÍKOVÁ, David POTĚŠIL, Lukáš TRANTÍREK, Zbyněk ZDRÁHAL, M. ELKALAF, J. TRNKA, Karel SOUČEK, N. RAUCH, J. RAUCH, W. KOLCH and Stjepan ULDRIJAN. Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. EMBO reports. Hoboken: Wiley-Blackwell, 2018, vol. 19, No 2, p. 320-336. ISSN 1469-221X. Available from: https://dx.doi.org/10.15252/embr.201744524.

@article{1409120,
   author = {Verlande, Amandine and Krafčíková, Michaela and Potěšil, David and Trantírek, Lukáš and Zdráhal, Zbyněk and Elkalaf, M. and Trnka, J. and Souček, Karel and Rauch, N. and Rauch, J. and Kolch, W. and Uldrijan, Stjepan},
   article_location = {Hoboken},
   article_number = {2},
   doi = {http://dx.doi.org/10.15252/embr.201744524},
   keywords = {cell cycle arrest; cell survival; melanoma; metabolic stress; RAF-ERK signaling},
   language = {eng},
   issn = {1469-221X},
   journal = {EMBO reports},
   title = {Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization},
   volume = {19},
   year = {2018}
}

TY  - JOUR
ID  - 1409120
AU  - Verlande, Amandine - Krafčíková, Michaela - Potěšil, David - Trantírek, Lukáš - Zdráhal, Zbyněk - Elkalaf, M. - Trnka, J. - Souček, Karel - Rauch, N. - Rauch, J. - Kolch, W. - Uldrijan, Stjepan
PY  - 2018
TI  - Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization
JF  - EMBO reports
VL  - 19
IS  - 2
SP  - 320-336
EP  - 320-336
PB  - Wiley-Blackwell
SN  - 1469221X
KW  - cell cycle arrest
KW  - cell survival
KW  - melanoma
KW  - metabolic stress
KW  - RAF-ERK signaling
N2  - Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS-mutant cells, and with oncogenic BRAF in BRAF(V600E)-mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS-mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAF(V600E)-mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary.
ER  -

VERLANDE, Amandine, Michaela KRAFČÍKOVÁ, David POTĚŠIL, Lukáš TRANTÍREK, Zbyněk ZDRÁHAL, M. ELKALAF, J. TRNKA, Karel SOUČEK, N. RAUCH, J. RAUCH, W. KOLCH and Stjepan ULDRIJAN. Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. \textit{EMBO reports}. Hoboken: Wiley-Blackwell, 2018, vol.~19, No~2, p.~320-336. ISSN~1469-221X. Available from: https://dx.doi.org/10.15252/embr.201744524.

Detailed Information on Publication Record