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 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status

“…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, 80–82). 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 (80–82), give further support to compensatory ERK reactivation as a key component of adaptive resistance to trametinib that can be inhibited by targeting KSR1.…”

“…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, 80–82). 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 (80–82), 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.…”

IQ Motif Containing GTPase Activating Proteins (IQGAPs), A-Kinase Anchoring Proteins (AKAPs) and Kinase Suppressor of Ras Proteins (KSRs) in Scaffolding Oncogenic Pathways and Their Therapeutic Potential

“…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 .…”

“…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.…”

PPA1 Promotes Breast Cancer Proliferation and Metastasis Through PI3K/AKT/GSK3β Signaling Pathway

“…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).…”