Fibroblast growth factor homologous factors and the islet brain-2 scaffold protein regulate activation of a stress-activated protein kinase

Abstract

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 p38δ (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 p38δ but not the MAPKs JNK-1 and p38α. Binding of p38δ to IB2 is mediated by the carboxyl-terminal half of the scaffold (IB2Δ1-436). FHF2 also binds weakly to IB2Δ1-436 and can thereby increase p38δ interaction with IB2Δ1-436. FHF-induced recruitment of p38δ to IB2 is accompanied by increased levels of activated p38δ, and synergistic activation of p38δ 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 p38δ in vitro. These results support the existence of a signaling module in which IB2 scaffolds a MLK3/MKK/p38δ kinase cascade. FHFs aid in recruitment of p38 to IB2 and may serve as kinase substrates.