Map kinase cascades function in eukaryotic cells to relay and translate extracellular signals into cellular biological responses. MAPKs include stress activated protein kinases (SAPKs) which can regulate cell shape, apoptosis, and neuromuscular coordination. FIP is a newly-isolated SAPK scaffold protein expressed in neuronal which has the unusual property of binding to fibroblast growth factor-homologous proteins (FHFs). In conjunction with FHF-2, FIP can coordinate the specific activation of SAPK4/p38delta by the upstream kinase MLK-3. Hence, while FHFs are structurally related to fibroblast growth factors, FHFs are hypothesized to function intracellularly as part of a SAPK kinase signalling module in neuronal cells. A series of mouse genetic experiments are proposed to investigate both the neurobiological function of FIP and its dependence upon FHFs to mediate SAPK4/p38delta activation. These experiments include (I) generation and analysis of FIP-deficient mice, (II) identification of FIP mutants incapable of binding FHF, and (III) generation and analysis of mice carrying such a mutation in FIP. In addition to the importance of defining the phenotype associated with disruption of a new biochemical pathway, these studies may significantly improve our understanding of mechanisms underlying neuronal development and function.
