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J. Biol. Chem., Vol. 280, Issue 26, 24690-24697, July 1, 2005

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Cellular Fibronectin Binds to Lysyl Oxidase with High Affinity and Is Critical for Its Proteolytic Activation^*

Ben Fogelgren, Noémi Polgár, Kornélia Molnárné Szauter, Zsuzsanna Újfaludi, Rozália Laczkó, Keith S. K. Fong, and Katalin Csiszar

From the Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, 96822

Lysyl oxidase (LOX) is a copper-containing amine oxidase known to catalyze the covalent cross-linking of fibrillar collagens and elastin at peptidyl lysine residues. In addition, its involvement in cancer, wound healing, cell motility, chemotaxis, and differentiation reflect a remarkable functional diversity of LOX. To investigate novel mechanisms of LOX regulation and function, we performed a yeast two-hybrid screen to identify LOX-interacting proteins. Three overlapping positive clones were identified as C-terminal fragments of fibronectin (FN). Glutathione S-transferase pull-downs and solid phase binding assays confirmed this interaction. LOX binds to the cellular form of FN (cFN) with a dissociation constant (K_d) of 2.5 nM. This was comparable with our measured K_d of LOX binding to tropoelastin (1.9 nM) and type I collagen (5.2 nM), but LOX demonstrated a much lower binding affinity for the plasma form of FN (pFN). Immunofluorescent microscopy revealed co-localization of FN and LOX in normal human tissues, where these proteins may interact in vivo. LOX enzymatic activity assays showed that cFN does not seem to be a substrate of LOX. However, cFN can act as a scaffold for enzymatically active 30-kDa LOX. Furthermore, in FN-null mouse embryonic fibroblasts, we observed dramatically decreased proteolytic processing of the 45-kDa LOX proenzyme to the 30-kDa active form, with a corresponding decrease in LOX enzyme activity. Our results suggest that the FN matrix may provide specific microenvironments to regulate LOX catalytic activity.

Received for publication, November 17, 2004 , and in revised form, April 1, 2005.

^* These studies were supported by Grants AR47713 and G12RR03961 from the National Institutes of Health (to K. C.) and by a Fellowship 0315258Z from the American Heart Association (to B. F.). 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.

To whom correspondence should be addressed: Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, 1960 East-West Rd., Biomed T311, Honolulu, HI 96822. Tel.: 808-956-9452; Fax: 808-956-9481; E-mail: Kcsiszar{at}aol.com.

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