ArticleThe Journal of biological chemistry2011
Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 81 citations in OpenAlex.
- Conserved and rewired MAPK networks in human fungal pathogens.FEMS yeast research · 2026Review
- Refined Phylogenetic Ortholog Inference Reveals Coevolutionary Expansion of the MAPK Signaling Network Through Finetuning of Pathway Specificity.Journal of molecular evolution · 2025Article
- Atypical MAPKs in cancer.The FEBS journal · 2025Review
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- Presynaptic Rac1 in the hippocampus selectively regulates working memory.bioRxiv : the preprint server for biology · 2024Article
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- The role of atypical MAP kinase 4 in the host interaction with Cryptosporidium parvum.Scientific reports · 2023Article
- ERK3 and DGKζ interact to modulate cell motility in lung cancer cells.Frontiers in cell and developmental biology · 2023Article
- Signaling pathways and therapeutic interventions in gastric cancer.Signal transduction and targeted therapy · 2022Review
- TLK1-mediated MK5-S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies.Molecular oncology · 2022Article
- Conditional ERK3 overexpression cooperates with PTEN deletion to promote lung adenocarcinoma formation in mice.Molecular oncology · 2022Article
- MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade.Nature communications · 2022Article
- MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.Science advances · 2021Article
- Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Dynamic Control Balancing Cell Proliferation and Inflammation is Crucial for an Effective Immune Response to Malaria.Frontiers in molecular biosciences · 2021Article
- Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3.International journal of molecular sciences · 2020Article
- Phosphorylation of steroid receptor coactivator-3 (SRC-3) at serine 857 is regulated by the p38Scientific reports · 2020Article
- The C-Terminus Tail Regulates ERK3 Kinase Activity and Its Ability in Promoting Cancer Cell Migration and Invasion.International journal of molecular sciences · 2020Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Classical mitogen-activated protein (MAP) kinases are activated by dual phosphorylation of the Thr-Xxx-Tyr motif in their activation loop, which is catalyzed by members of the MAP kinase kinase family. The atypical MAP kinases extracellular signal-regulated kinase 3 (ERK3) and ERK4 contain a single phospho-acceptor site in this segment and are not substrates of MAP kinase kinases. Previous studies have shown that ERK3 and ERK4 are phosphorylated on activation loop residue Ser-189/Ser-186, resulting in their catalytic activation. However, the identity of the protein kinase mediating this regulatory event has remained elusive. We have used an unbiased biochemical purification approach to isolate the kinase activity responsible for ERK3 Ser-189 phosphorylation. Here, we report the identification of group I p21-activated kinases (PAKs) as ERK3/ERK4 activation loop kinases. We show that group I PAKs phosphorylate ERK3 and ERK4 on Ser-189 and Ser-186, respectively, both in vitro and in vivo, and that expression of activated Rac1 augments this response. Reciprocally, silencing of PAK1/2/3 expression by RNA interference (RNAi) completely abolishes Rac1-induced Ser-189 phosphorylation of ERK3. Importantly, we demonstrate that PAK-mediated phosphorylation of ERK3/ERK4 results in their enzymatic activation and in downstream activation of MAP kinase-activated protein kinase 5 (MK5) in vivo. Our results reveal that group I PAKs act as upstream activators of ERK3 and ERK4 and unravel a novel PAK-ERK3/ERK4-MK5 signaling pathway.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.