KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. / Vaseva, Angelina V; Blake, Devon R; Gilbert, Thomas S K; Ng, Serina; Hostetter, Galen; Azam, Salma H; Ozkan-Dagliyan, Irem; Gautam, Prson; Bryant, Kirsten L; Pearce, Kenneth H; Herring, Laura E; Han, Haiyong; Graves, Lee M; Witkiewicz, Agnieszka K; Knudsen, Erik S; Pecot, Chad V; Rashid, Naim; Houghton, Peter J; Wennerberg, Krister; Cox, Adrienne D; Der, Channing J.
I: Cancer Cell, Bind 34, Nr. 5, 2018, s. 807-822.e1-e7.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism
AU - Vaseva, Angelina V
AU - Blake, Devon R
AU - Gilbert, Thomas S K
AU - Ng, Serina
AU - Hostetter, Galen
AU - Azam, Salma H
AU - Ozkan-Dagliyan, Irem
AU - Gautam, Prson
AU - Bryant, Kirsten L
AU - Pearce, Kenneth H
AU - Herring, Laura E
AU - Han, Haiyong
AU - Graves, Lee M
AU - Witkiewicz, Agnieszka K
AU - Knudsen, Erik S
AU - Pecot, Chad V
AU - Rashid, Naim
AU - Houghton, Peter J
AU - Wennerberg, Krister
AU - Cox, Adrienne D
AU - Der, Channing J
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018
Y1 - 2018
N2 - Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.
AB - Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.
U2 - 10.1016/j.ccell.2018.10.001
DO - 10.1016/j.ccell.2018.10.001
M3 - Journal article
C2 - 30423298
VL - 34
SP - 807-822.e1-e7
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -
ID: 215091591