Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions incellular communication and signal transduction

The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum of extracellular ligands, Traditionally, they had been reg arded as mere cargo receptors that promote the endocytosis and lysosomal de livery of these ligands, However, recent genetic experiments in mice have r evealed critical functions for two LDL receptor family members, the very lo w density lipoprotein receptor and the apoE receptor-a, in the transmission of extracellular signals and the activation of intracellular tyrosine kina ses, This process regulates neuronal migration and is crucial for brain dev elopment. Signaling through these receptors requires the interaction of the ir cytoplasmic tails with the intracellular adaptor protein Disabled-1 (DAB 1), Here, we identify an extended set of cytoplasmic proteins that might al so participate in signal transmission by the LDL receptor gene family. Most of these novel proteins are adaptor or scaffold proteins that contain PID or PDZ domains and function in the regulation of mitogen-activated protein kinases, cell adhesion, vesicle trafficking, or neurotransmission, We show that binding of DAB1 interferes with receptor internalization suggesting a mechanism by which signaling through this class of receptors might be regul ated. Taken together, these findings imply much broader physiological funct ions for the LDL receptor family than had previously been appreciated. They form the basis for the elucidation of the molecular pathways by which cell s respond to the diversity of ligands that bind to these multifunctional re ceptors on the cell surface.