2021
DOI: 10.7554/elife.66608
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KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition

Abstract: The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 signi… Show more

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Cited by 14 publications
(13 citation statements)
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References 77 publications
(147 reference statements)
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“…This finding is consistent with KSR1 function as a RAF/MEK/ERK scaffold and with our previous studies showing KSR1-ERK signaling is essential to mutant RAS -driven transformation (38, 40, 8082). These findings, when coupled to our previous data showing that PI3K/AKT signaling was independent of KSR1 (38, 40) and KSR1 depletion inhibited transformation in KRAS / PIK3CA co-mutated COAD cells (8082), give further support to compensatory ERK reactivation as a key component of adaptive resistance to trametinib that can be inhibited by targeting KSR1.…”
Section: Discussionsupporting
confidence: 93%
See 1 more Smart Citation
“…This finding is consistent with KSR1 function as a RAF/MEK/ERK scaffold and with our previous studies showing KSR1-ERK signaling is essential to mutant RAS -driven transformation (38, 40, 8082). These findings, when coupled to our previous data showing that PI3K/AKT signaling was independent of KSR1 (38, 40) and KSR1 depletion inhibited transformation in KRAS / PIK3CA co-mutated COAD cells (8082), give further support to compensatory ERK reactivation as a key component of adaptive resistance to trametinib that can be inhibited by targeting KSR1.…”
Section: Discussionsupporting
confidence: 93%
“…This finding is consistent with KSR1 function as a RAF/MEK/ERK scaffold and with our previous studies showing KSR1-ERK signaling is essential to mutant RAS -driven transformation (38, 40, 8082). These findings, when coupled to our previous data showing that PI3K/AKT signaling was independent of KSR1 (38, 40) and KSR1 depletion inhibited transformation in KRAS / PIK3CA co-mutated COAD cells (8082), give further support to compensatory ERK reactivation as a key component of adaptive resistance to trametinib that can be inhibited by targeting KSR1. Further, the finding that ksr1 −/− mice are phenotypically normal but resistant to cancer formation (41, 42) highlights the potential of targeting KSR1 to achieve a high therapeutic index.…”
Section: Discussionsupporting
confidence: 93%
“…Epithelial-stromal interaction 1 (EPSTI1) is required to trigger the transition from E- to N-cadherin. KSR1-mediated activation of ERK increases EPSTI1 protein levels, which promotes EMT-like phenotype in colorectal cancer . In pancreatic cancer, a contradictory effect of KSR1 on ERK activation has been observed in different studies .…”
Section: Scaffold Proteins In Humansmentioning
confidence: 99%
“…KSR1-mediated activation of ERK increases EPSTI1 protein levels, which promotes EMT-like phenotype in colorectal cancer. 83 In pancreatic cancer, a contradictory effect of KSR1 on ERK activation has been observed in different studies. 84 In one study, the knockout of KSR1 did not affect phospho-ERK levels.…”
Section: Scaffold Proteins In Humansmentioning
confidence: 99%
“…Slug is one of the critical regulators which lead to EMT and is closely related to cancer metastasis. It induces EMT by repressing the expression of E-cadherin (Rao et al, 2021). Slug is also involved in various cellular processes, including neural crest cell migration and mesoderm formation (Reece-Hoyes et al, 2009;Ke et al, 2019;Flach et al, 2021).…”
Section: Proposed Model Of Ppa1 In Breast Cancer Progressionmentioning
confidence: 99%