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J. Biol. Chem., Vol. 279, Issue 11, 10005-10012, March 12, 2004

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Low Density Lipoprotein Receptor-related Protein-1 Promotes ₁ Integrin Maturation and Transport to the Cell Surface^*

Ana María Salicioni, Alban Gaultier, Cristina Brownlee, Michael K. Cheezum, and Steven L. Gonias¶

From the Departments of Pathology and Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Low density lipoprotein receptor-related protein-1 (LRP-1) mediates the endocytosis of multiple plasma membrane proteins and thereby models the composition of the cell surface. LRP-1 also functions as a catabolic receptor for fibronectin, limiting fibronectin accumulation in association with cells. The goal of the present study was to determine whether LRP-1 regulates cell surface levels of the ₁ integrin subunit. We hypothesized that LRP-1 may down-regulate cell surface ₁ by promoting its internalization; however, unexpectedly, LRP-1 expression was associated with a substantial increase in cell surface ₁ integrin in two separate cell lines, murine embryonic fibroblasts (MEFs) and CHO cells. The total amount of ₁ integrin was unchanged because LRP-1-deficient cells retained increased amounts of ₁ in the endoplasmic reticulum (ER). Expression of human LRP-1 in LRP-1-deficient MEFs reversed the shift in subcellular ₁ integrin distribution. Metabolic labeling experiments demonstrated that the precursor form of newly synthesized ₁ integrin (p105) is converted into mature ₁ (p125) more slowly in LRP-1-deficient cells. Although low levels of cell surface ₁ integrin, in LRP-1-deficient MEFs, were associated with decreased adhesion to fibronectin, the subcellular distribution of ₁ integrin was most profoundly dependent on LRP-1 only after the cell cultures became confluent. A mutagen-treated CHO cell line, in which LRP-1 is expressed but retained in the secretory pathway, also demonstrated nearly complete ER retention of ₁ integrin. These studies support a model in which LRP-1 either directly or indirectly promotes maturation of ₁ integrin precursor and thereby increases the level of ₁ integrin at the cell surface.

Received for publication, June 23, 2003 , and in revised form, December 1, 2003.

^* 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.

These authors contributed equally to this work.

Present address: University of Massachusetts, Paige Laboratories, 161 Holdsworth Way, Amherst, MA 01003.

^¶ To whom correspondence should be addressed: University of Virginia School of Medicine, Dept. of Pathology, Box 800214, Charlottesville, VA 22908. Tel.: 434-924-9192; Fax: 434-982-0283; E-mail: slg2t{at}virginia.edu.

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