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Molecular and Cellular Biology, May 2004, p. 3782-3793, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3782-3793.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Peter Marschang,^1, Jochen Brich,^1, Edwin J. Weeber,² J. David Sweatt,² John M. Shelton,³ James A. Richardson,⁴ Robert E. Hammer,⁵ and Joachim Herz^1*

Departments of Molecular Genetics,¹ Internal Medicine,³ Pathology,⁴ Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390,⁵ Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030²

Received 9 January 2004/ Returned for modification 22 January 2004/ Accepted 5 February 2004

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.

Present address: Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria.

Present address: Zentrum für Neurowissenschaften, Universität Freiburg, 79104 Freiburg, Germany.

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