Fibroblast growth factor homologous factors and the islet brain-2 scaffold protein regulate activation of a stress-activated protein kinase.
Fibroblast growth factor homologous factors (FHFs) form native intracellular complexes with the mitogen-activated protein kinase (MAPK) scaffold protein islet-brain 2 (IB2) in adult brain. FHF binding to IB2 facilitates recruitment of the MAPK p38delta (SAPK4), while failing to stimulate binding of JNK, the preferred kinase of the related scaffold IB1 ... (JIP-1). We now report further biochemical evidence supporting FHFs as regulators of IB2 scaffold activity. Mixed lineage kinase 3 (MLK3) and IB2 synergistically activate p38delta but not the MAPKs JNK-1 and p38alpha. Binding of p38delta to IB2 is mediated by the carboxyl-terminal half of the scaffold (IB2(Delta1-436)). FHF2 also binds weakly to IB2(Delta1-436) and can thereby increase p38delta interaction with IB2(Delta1-436). FHF-induced recruitment of p38delta to IB2 is accompanied by increased levels of activated p38delta, and synergistic activation of p38delta by MLK3 and IB2 is further enhanced by FHF2. Consistent with a role for FHFs as signaling molecules, FHF2 isolated from rat brain is serine/threonine-phosphorylated, and FHF can serve as a substrate for p38delta in vitro. These results support the existence of a signaling module in which IB2 scaffolds a MLK3/MKK/p38delta kinase cascade. FHFs aid in recruitment of p38 to IB2 and may serve as kinase substrates.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Alternative Splicing, Animals, Binding Sites, Blotting, Western, Brain, Carrier Proteins, Cell Line, Cerebellum, Cerebral Cortex, Enzyme Activation, Gene Expression Regulation, Enzymologic, Genetic Vectors, Humans, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase 13, Mitogen-Activated Protein Kinase 14, Mitogen-Activated Protein Kinases, Models, Genetic, Phosphorylation, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Rats, Signal Transduction, Substrate Specificity, Transfection, p38 Mitogen-Activated Protein Kinases
Adaptor Proteins, Signal Transducing, Alternative Splicing, Animals, Binding Sites, Blotting, Western, Brain, Carrier Proteins, Cell Line, Cerebellum, Cerebral Cortex, Enzyme Activation, Gene Expression Regulation, Enzymologic, Genetic Vectors, Humans, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase 13, Mitogen-Activated Protein Kinase 14, Mitogen-Activated Protein Kinases, Models, Genetic, Phosphorylation, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Rats, Signal Transduction, Substrate Specificity, Transfection, p38 Mitogen-Activated Protein Kinases
J. Biol. Chem.
Date: Dec. 20, 2002
PubMed ID: 12244047
View in: Pubmed Google Scholar
Download Curated Data For This Publication
8512
Switch View:
- Interactions 4