Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transduction occurs by the reversible assembly of oligomeric protein complexes that include both enzymatic proteins and proteins without known enzymatic activity. These nonenzymatic components can serve as scaffolds or anchors and regulate the efficiency, specificity, and localization of the signaling pathway. Here we report the identification of MORG1 (mitogen-activated protein kinase organizer 1), a member of the WD-40 protein family that was isolated as a binding partner of the extracellular signal-regulated kinase (ERK) pathway scaffold protein MP1. MORG1 specifically associates with several components of the ERK pathway, including MP1, Raf-1, MEK, and ERK, and stabilizes their assembly into an oligomeric complex. MORG1 facilitates ERK activation when cells are stimulated with lysophosphatidic acid, phorbol 12-myristate 13-acetate, or serum, but not in response to epidermal growth factor. Suppression of MORG1 by short interfering RNA leads to a marked reduction in ERK activity when cells are stimulated with serum. We propose that MORG1 is a component of a modular scaffold system that participates in the regulation of agonist-specific ERK signaling.
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PMID:Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists. 1511 98

Leishmania amazonensis infection promotes alteration of host cellular signaling and intracellular parasite survival, but specific mechanisms are poorly understood. We previously demonstrated that L. amazonensis infection of dendritic cells (DC) activated extracellular signal-regulated kinase (ERK), an MAP-kinase kinase kinase, leading to altered DC maturation and non-healing cutaneous leishmaniasis. Studies using growth factors and cell lines have shown that targeted, robust, intracellular phosphorylation of ERK1/2 from phagolysosomes required recruitment and association with scaffolding proteins, including p14/MP1 and MORG1, on the surface of late endosomes. Based on the intracellular localization of L. amazonensis within a parasitophorous vacuole with late endosome characteristics, we speculated that scaffolding proteins would be important for intracellular parasite-mediated ERK signaling. Our findings demonstrate that MP1, MORG1, and ERK all co-localized on the surface of parasite-containing LAMP2-positive phagolysosomes. Infection of MEK1 mutant fibroblasts unable to bind MP1 demonstrated dramatically reduced ERK1/2 phosphorylation following L. amazonensis infection but not following positive control EGF treatment. This novel mechanism for localization of intracellular L. amazonensis-mediated ERK1/2 phosphorylation required the endosomal scaffold protein MP1 and localized to L. amazonensis parasitophorous vacuoles. Understanding how L. amazonensis parasites hijack host cell scaffold proteins to modulate signaling cascades provides targets for antiprotozoal drug development.
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PMID:Targeted extracellular signal-regulated kinase activation mediated by Leishmania amazonensis requires MP1 scaffold. 2446 70