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J. Biol. Chem., Vol. 283, Issue 35, 24103-24117, August 29, 2008

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Lysyl Oxidase Oxidizes Cell Membrane Proteins and Enhances the Chemotactic Response of Vascular Smooth Muscle Cells^*

Héctor A. Lucero¹, Katya Ravid², Jessica L. Grimsby, Celeste B. Rich, Sandra J. DiCamillo, Joni M. Mäki, Johanna Myllyharju, and Herbert M. Kagan

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118 and the Collagen Research Unit, Biocenter Oulu and Department of Medical, Biochemistry and Molecular Biology, University of Oulu, Oulu FIN-90014, Finland

Lysyl oxidase (LOX) is a potent chemokine inducing the migration of varied cell types. Here we demonstrate that inhibition of LOX activity by β-aminopropionitrile (BAPN) in cultured rat aortic smooth muscle cells (SMCs) reduced the chemotactic response and sensitivity of these cells toward LOX and toward PDGF-BB. The chemotactic activity of PDGF-BB was significantly enhanced in the presence of a non-chemotactic concentration of LOX. We considered the possibility that extracellular LOX may oxidize cell surface proteins, including the PDGF receptor-β (PDGFR-β), to affect PDGF-BB-induced chemotaxis. Plasma membranes purified from control SMC contained oxidized PDGFR-β. The oxidation of this receptor and other membrane proteins was largely prevented in cells preincubated with BAPN. Addition of purified LOX to these cells restored the profile of oxidized proteins toward that of control cells. The high affinity and capacity for the binding of PDGF-BB by cells containing oxidized PDGFR-β was diminished by 2-fold when compared with cells in which oxidation by LOX was prevented by BAPN. Phosphorylated members of the PDGFR-β-dependent signal transduction pathway, including PDGFR-β, SHP2, AKT1, and ERK1/ERK2 (p44/42 MAPK), turned over faster in BAPN-treated than in control SMCs. LOX knock-out mouse embryonic fibroblasts mirrored the effect obtained with SMCs treated with BAPN. These novel findings suggest that LOX activity is essential to generate optimal chemotactic sensitivity of cells to chemoattractants by oxidizing specific cell surface proteins, such as PDGFR-β.

Received for publication, December 4, 2007 , and in revised form, June 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL13262-31 (to H. K. and K. R.). 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.

² An Established Investigator with the American Heart Association.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4111; Fax: 617-638-5339; E-mail: hlucero{at}bu.edu.

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