ArticleThe Journal of biological chemistry2009
Noncatalytic function of ERK1/2 can promote Raf/MEK/ERK-mediated growth arrest signaling.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Long Noncoding RNA MALAT-1 Can Predict Metastasis and a Poor Prognosis: a Meta-Analysis.Pathology oncology research : POR · 2015Pooled it
- STUB1-induced polyubiquitination of SIK3 in alveolar type 2 epithelial cells alleviates severity and outcomes of acute lung injury.Cell death & disease · 2026Article
- ERKed by too much signaling: from oncogenic driver to therapeutic vulnerability.Cellular and molecular life sciences : CMLS · 2026Review
- Decoding allosteric landscapes: computational methodologies for enzyme modulation and drug discovery.RSC chemical biology · 2025Review
- ERK1/2 interaction with DHPS regulates eIF5A deoxyhypusination independently of ERK kinase activity.Cell reports · 2024Article
- Estrogen-related receptor alpha promotes thyroid tumor cell survival via a tumor subtype-specific regulation of target gene networks.Oncogene · 2024Article
- ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework.NPJ precision oncology · 2024Review
- Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET-mutant thyroid cancer.NPJ precision oncology · 2024Article
- GRM2 Regulates Functional Integration of Adult-Born DGCs by Paradoxically Modulating MEK/ERK1/2 Pathway.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Prolonged warm ischemia time increases mitogen-activated protein kinase activity and decreases perfusate cytokine levels inFrontiers in transplantation · 2023Article
- Analogs of the Heat Shock Protein 70 Inhibitor MKT-077 Suppress Medullary Thyroid Carcinoma Cells.International journal of molecular sciences · 2022Article
- eIF5A-Independent Role of DHPS in p21International journal of molecular sciences · 2021Article
- A multiple network-based bioinformatics pipeline for the study of molecular mechanisms in oncological diseases for personalized medicine.Briefings in bioinformatics · 2021Article
- Mortalin depletion induces MEK/ERK-dependent and ANT/CypD-mediated death in vemurafenib-resistant B-RafCancer letters · 2021Article
- Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology.Cellular and molecular life sciences : CMLS · 2021Review
- Growth Inhibitory Signaling of the Raf/MEK/ERK Pathway.International journal of molecular sciences · 2020Review
- Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability.Oncogene · 2020Article
- Mortalin (HSPA9) facilitatesScience signaling · 2020Article
- Downregulation of CKS1B restrains the proliferation, migration, invasion and angiogenesis of retinoblastoma cells through the MEK/ERK signaling pathway.International journal of molecular medicine · 2019Article
- Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells.International journal of molecular sciences · 2019Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Kinase activity is known as the key biochemical property of MAPKs. Here, we report that ERK1/2 also utilizes its noncatalytic function to mediate certain signal transductions. Sustained activation of the Raf/MEK/ERK pathway induces growth arrest, accompanied by changes in cell cycle regulators (decreased retinoblastoma phosphorylation, E2F1 down-regulation, and/or p21(CIP1) up-regulation) and cell type-specific changes in morphology and expression of c-Myc or RET in the human tumor lines LNCaP, U251, and TT. Ablation of ERK1/2 by RNA interference abrogated all these effects. However, active site-disabled ERK mutants (ERK1-K71R, ERK2-K52R, and ERK2-D147A), which competitively inhibit activation of endogenous ERK1/2, could not block Raf/MEK-induced growth arrest as well as changes in the cell cycle regulators, although they effectively blocked phosphorylation of the ERK1/2 catalytic activity readouts, p90(RSK) and ELK1, as well as the cell type-specific changes. Because this indicated a potential noncatalytic ERK1/2 function, we generated stable lines of the tumor cells in which both ERK1 and ERK2 were significantly knocked down, and we further investigated the possibility using rat-derived kinase-deficient ERK mutants (ERK2-K52R and ERK2-T183A/Y185F) that were not targeted by human small hairpin RNA. Indeed, ERK2-K52R selectively restored Raf-induced growth inhibitory signaling in ERK1/2-depleted cells, as manifested by regained cellular ability to undergo growth arrest and to control the cell cycle regulators without affecting c-Myc and morphology. However, ERK2-T183A/Y185F was less effective, indicating the requirement of TEY site phosphorylation. Our study suggests that functions of ERK1/2 other than its "canonical" kinase activity are also involved in the pathway-mediated growth arrest signaling.
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