The LIS1/NDE1 Complex Is Essential for FGF Signaling by Regulating FGF Receptor Intracellular Trafficking

Abstract

Summary: Intracellular transport of membranous organelles and protein complexes to various destinations is fundamental to signaling transduction and cellular function. The cytoplasmic dynein motor and its regulatory proteins LIS1 and NDE1 are required for transporting a variety of cellular cargos along the microtubule network. In this study, we show that deletion of Lis1 in developing lung endoderm and limb mesenchymal cells causes agenesis of the lungs and limbs. In both mutants, there is increased cell death and decreased fibroblast growth factor (FGF) signaling activity. Mechanistically, LIS1 and its interacting protein NDE1/NDEL1 are associated with FGF receptor-containing vesicles and regulate FGF receptor intracellular trafficking and degradation. Notably, FGF signaling promotes NDE1 tyrosine phosphorylation, which leads to dissociation of LIS1/NDE1 complex. Thus, our studies identify the LIS1/NDE1 complex as an important FGF signaling regulator and provide insights into the bidirectional regulation of cell signaling and transport machinery for endocytosis. : Liu et al. show that Lis1 is required for mouse embryonic lung and limb formation. The LIS1/NDE1/dynein complex regulates FGF receptor trafficking and stability. FGF signaling promotes NDE1 tyrosine phosphorylation, which leads to dissociation of the LIS1/NDE1 complex, suggesting a bidirectional regulation of cell signaling and transport machinery. Keywords: LIS1, NDE1, dynein, FGF signaling, development, endocytosis