Normal Development and Fertility of Knockout Mice Lacking the Tumor Suppressor Gene LRP1b Suggest Functional Compensation by LRP1

Abstract

LRP1b and the closely related LRP1 are large members of the low-density lipoprotein receptor family. At the protein level LRP1b is 55% identical to LRP1, a multifunctional and developmentally essential receptor with roles in cargo transport and cellular signaling. Somatic LRP1b mutations frequently occur in non-small cell lung cancer and urothelial cancers, suggesting a role in the modulation of cellular growth. In contrast to LRP1, LRP1b-deficient mice develop normally, most likely due to its restricted expression pattern and functional compensation by LRP1 or other receptors. LRP1b is expressed predominantly in the brain, and a differentially spliced form is present in the adrenal gland and in the testis. Despite the presence of a potential furin cleavage site and in contrast to LRP1, immunoblotting for LRP1b reveals the presence of a single 600-kDa polypeptide species. Using a yeast two-hybrid approach, we have identified two intracellular proteins, the postsynaptic density protein 95 and the aryl hydrocarbon receptor-interacting protein, that bind to the intracellular domain of LRP1b. In addition, we have found several potential ligands that bind to the extracellular domain. Analysis of LRP1b knockout mice may provide further insights into the role of LRP1b as a tumor suppressor and into the mechanisms of cancer development.

We are indebted to LaMetria Blair for excellent technical assistance and Wen-Ling Niu for valuable advice with some of the experiments. We thank Oliver Bergner for help with the expression of GST fusion proteins and Chris Pomajzl for assistance with the brain histology. Thomas C. Südhof generously provided the PSD-95 plasmid.

P.M. received an Erwin Schroedinger fellowship (J1950-PAT and J2162) from the Austrian FWF. J.B. was supported by the Boehringer Ingelheim Foundation. This study was supported by grants from the NIH (HL20948, HL63762, NS43408), the Alzheimer Association, and the Perot Family Foundation.