Skipping Transcription with Megalin-Binding Protein

Abstract

Peterson et al. developed an intriguing model whereby the endocytotic receptor megalin participates in the controlled sequestration and release of transcription factors. Megalin, a member of the low density lipoprotein (LDL) receptor family, has numerous ligands and may be involved in diverse functions from resorption of vitamin D metabolites in the kidney to transmitting signals from the morphogenetic protein sonic hedgehog during brain development. Peterson et al. used a yeast two-hybrid screen to identify a protein containing two tetratrico peptide repeats--motifs involved in protein-to-protein interactions--that bound to megalin's cytoplasmic tail, which they named megalin-binding protein (MegBP). The authors expressed fluorescently labeled MegBP in BN16 cells, a cell line that produces large amounts of megalin, to show colocalization of MegBP with immunofluorescently labeled megalin. MegBP overexpression did not inhibit endocytosis of a fluorescently labeled ligand 4 hours after transfection, but was lethal to cell lines containing high levels of endogenous megalin within 24 hours. Further screens identified several other proteins that bound to MegBP, including transcriptional regulators and components of signal transduction pathways. One of these MegBP binding partners, SKI-interacting protein (SKIP), is a coactivator of the vitamin D receptor. The authors proposed a model whereby SKIP is sequestered by MegBP to the megalin receptor tail and released after endocytosis of vitamin D metabolites so that it is free to interact with the vitamin D receptor. In this model, the lethal effects of MegBP overexpression could result from uncontrolled sequestration of SKIP and other transcriptional regulators. H. H. Peterson, J. Hilpert, D. Militz, V. Zandler, C. Jacobsen, A. J. M. Roebroek, T. E. Wilnow, Functional interaction of megalin with the megalin-binding protein (MegBP), a novel tetratrico peptide repeat-containing adaptor molecule. J. Cell Sci. 116 , 453-461 (2003). [Abstract] [Full Text]