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.

Základní údaje

Originální název

Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization

Autoři

VERLANDE, Amandine (250 Francie, domácí), Michaela KRAFČÍKOVÁ (703 Slovensko, domácí), David POTĚŠIL (203 Česká republika, domácí), Lukáš TRANTÍREK (203 Česká republika, domácí), Zbyněk ZDRÁHAL (203 Česká republika, domácí), M. ELKALAF (203 Česká republika), J. TRNKA (203 Česká republika), Karel SOUČEK (203 Česká republika, domácí), N. RAUCH (372 Irsko), J. RAUCH (372 Irsko), W. KOLCH (372 Irsko) a Stjepan ULDRIJAN (203 Česká republika, garant, domácí)

Vydání

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

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

Impakt faktor

Impact factor: 8.383

Kód RIV

RIV/00216224:14110/18:00100832

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000424166400015

Klíčová slova anglicky

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

Štítky

14110513, EL OK, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 6. 3. 2019 13:35, Mgr. Pavla Foltynová, Ph.D.

Anotace

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.

Návaznosti

GA14-12166S, projekt VaV

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

Investor: Grantová agentura ČR, Regulace dráhy nádorového supresoru p53 novými vazebnými partnery onkogenů Mdm2 a Mdm4

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

MUNI/A/0810/2016, interní kód MU

Název: Molekulární a buněčná biologie

Investor: Masarykova univerzita, Molekulární a buněčná biologie, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

Citovat

VERLANDE, Amandine, Michaela KRAFČÍKOVÁ, David POTĚŠIL, Lukáš TRANTÍREK, Zbyněk ZDRÁHAL, M. ELKALAF, J. TRNKA, Karel SOUČEK, N. RAUCH, J. RAUCH, W. KOLCH a Stjepan ULDRIJAN. Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. EMBO reports. Hoboken: Wiley-Blackwell, 2018, roč. 19, č. 2, s. 320-336. ISSN 1469-221X. Dostupné z: 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 a Stjepan ULDRIJAN. Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. \textit{EMBO reports}. Hoboken: Wiley-Blackwell, 2018, roč.~19, č.~2, s.~320-336. ISSN~1469-221X. Dostupné z: https://dx.doi.org/10.15252/embr.201744524.

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