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J. Biol. Chem., Vol. 281, Issue 11, 7332-7340, March 17, 2006

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Regulation of the Composition of the Extracellular Matrix by Low Density Lipoprotein Receptor-related Protein-1

ACTIVITIES BASED ON REGULATION OF mRNA EXPRESSION^*

Alban Gaultier, Ana Maria Salicioni, Sanja Arandjelovic, and Steven L. Gonias¹

From the Department of Pathology, University of California San Diego School of Medicine, La Jolla, California 92093 and the Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003

Low density lipoprotein receptor-related protein-1 (LRP-1) is a catabolic receptor for extracellular matrix (ECM) structural proteins and for proteins that bind to ECM. LRP-1 also is implicated in integrin maturation. In this study, we applied a proteomics strategy to identify novel proteins involved in ECM modeling that are regulated by LRP-1. We show that LRP-1 deficiency in murine embryonic fibroblasts (MEFs) is associated with increased levels of type III collagen and pigment epithelium-derived factor, which accumulate in the substratum surrounding cells. The collagen receptor, uPAR-AP/Endo-180, is also increased in LRP-1-deficient MEFs. Human LRP-1 reversed the changes in protein expression associated with LRP-1 deficiency; however, the endocytic activity of LRP-1 was not involved. Instead, regulation occurred at the mRNA level. Inhibition of c-Jun amino-terminal kinase (JNK) blocked type III collagen expression in LRP-1-deficient MEFs, suggesting regulation of JNK activity as a mechanism by which LRP-1 controls mRNA expression. The ability of LRP-1 to regulate expression of the factors identified here suggests a role for LRP-1 in determining blood vessel structure and in angiogenesis.

Received for publication, November 3, 2005

^* This work was supported by Grant R01 HL60551 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093. Tel.: 858-534-1887; Fax: 858-534-0414; E-mail: sgonias{at}ucsd.edu.

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