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| MAPK/ERK | |
|---|---|
| Name | MAPK/ERK |
MAPK/ERK MAPK/ERK is a mitogen-activated protein kinase cascade central to eukaryotic signal transduction. It links surface receptors such as Epidermal growth factor receptor and Fibroblast growth factor receptor to nuclear effectors including Elk-1 and c-Fos, coordinating proliferation, differentiation, and survival. The pathway has been characterized through studies involving model organisms and institutions such as Max Planck Society, Cold Spring Harbor Laboratory, and Howard Hughes Medical Institute investigators.
The cascade was elucidated in work from groups at University of California, San Francisco, Harvard University, and Massachusetts Institute of Technology and integrates inputs from receptors like Platelet-derived growth factor receptor and Insulin receptor. It intersects with pathways described by researchers at National Institutes of Health, European Molecular Biology Laboratory, and Stanford University Medical Center, and is modulated by scaffolds and adaptors studied at Johns Hopkins University and University of Cambridge. Historical milestones involve authors from Cold Spring Harbor Laboratory Press and awardees of the Lasker Award.
ERK proteins are serine/threonine kinases sharing structural motifs characterized by studies at Protein Data Bank, European Bioinformatics Institute, and Swiss Institute of Bioinformatics. Structural analyses by groups at European Molecular Biology Laboratory and Max Planck Institute revealed conserved activation loops and docking domains that bind substrates such as Myc and Ets1. Biochemical properties were detailed in biochemical labs at Rockefeller University, Princeton University, and Yale University, and structural determinants map to regions analyzed by researchers associated with Cold Spring Harbor Laboratory, Scripps Research, and University of Oxford.
Activation begins at receptor tyrosine kinases like Epidermal growth factor receptor, recruiting adaptors such as Grb2 and Shc, with guanine nucleotide exchange factors like SOS1 activating small GTPases such as Ras (protein) family members including HRAS, KRAS, and NRAS. RAF kinases including ARAF, BRAF, and CRAF phosphorylate MEK1/2, which in turn phosphorylate ERK; key mechanistic insights come from laboratories at European Molecular Biology Laboratory, Dana-Farber Cancer Institute, and Cold Spring Harbor Laboratory. Crosstalk with pathways involving PI3K, AKT1, and mTOR was characterized in collaborations with Broad Institute and Wellcome Trust Sanger Institute teams.
ERK signaling controls cell cycle regulators such as Cyclin D1, p27Kip1, and E2F1, and modulates transcription factors like Elk-1, c-Fos, and Myc; physiological roles have been studied in contexts from Drosophila melanogaster development to mammalian systems examined at Massachusetts General Hospital and Children's Hospital Boston. In neuronal contexts, connections to plasticity implicate molecules studied at Columbia University and University College London, while cardiac development and hypertrophy research involves teams at Cleveland Clinic and Mayo Clinic. Immune system modulation and cytokine responses have been probed by investigators at Rockefeller University and Imperial College London.
Regulation involves phosphatases such as DUSP6 and MKP-1 and ubiquitin ligases characterized by scientists at National Cancer Institute and Fred Hutchinson Cancer Research Center. Negative feedback loops engage transcriptional regulators studied at University of Pennsylvania and University of Chicago, and scaffold proteins like KSR1 and IQGAP1 were described by teams at University of Cambridge and University of Toronto. Post-translational modifications including ubiquitination and SUMOylation have been elucidated by groups at Cold Spring Harbor Laboratory and European Molecular Biology Laboratory.
Aberrant signaling through the cascade is implicated in cancers driven by mutations in BRAF, KRAS, and NRAS, with targeted therapies developed by pharmaceutical companies and clinical trials at Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and MD Anderson Cancer Center. Inhibitors such as those targeting BRAF V600E were evaluated through collaborations involving Novartis and Roche; resistance mechanisms involve reactivation studied by consortia including AACR and ESMO. Roles in developmental disorders link to syndromes characterized by mutations described by clinicians at Johns Hopkins Hospital and Boston Children's Hospital.
Experimental dissection uses techniques from structural biology at Protein Data Bank and Cryo-Electron Microscopy Facility labs, and biochemical assays developed at Cold Spring Harbor Laboratory and EMBL-EBI. Genetic models include work in Drosophila melanogaster, Mus musculus, and Caenorhabditis elegans laboratories at institutions like The Francis Crick Institute, Max Planck Institute, and Salk Institute for Biological Studies. High-throughput screens and omics approaches leveraging resources at Broad Institute, Wellcome Trust Sanger Institute, and European Molecular Biology Laboratory define pathway interactions, while clinical assays are standardized in labs at Mayo Clinic and Cleveland Clinic.