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The members of the low density lipoprotein receptor (LDLR) gene family are cell surface molecules with diverse functions in cellular metabolism. All LDLR family members are endocytic receptors that mediate the uptake of extracellular cargo into the cell; recent research indicates that they also participate directly in signal transduction. Regulated proteolytic release of the intracellular domain of one of these lipoprotein receptors, the LDLR-related protein 1 (LRP1), has been described, along with the possible role of the released domain in transcriptional regulation. A recent study suggests that megalin, a member of the LDLR gene family that mediates the cellular uptake of vitamin D carrier protein, may also modulate vitamin D-related gene transcription through sequestration of a component of the vitamin D receptor transcriptional complex. May et al. discuss this research in the context of the integration of endocytosis and signaling by this receptor family.