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Contrasting Roles for Domain 4 of VCAM-1 in the Regulation of Cell Adhesion and Soluble VCAM-1 Binding to Integrin ₄₁¹

Darren G. Woodside^2,*, Ronda M. Kram^*, Jason S. Mitchell, Tracie Belsom^*, Matthew J. Billard, Bradley W. McIntyre and Peter Vanderslice^*

^* Encysive Pharmaceuticals Incorporated, Houston, TX 77030; and University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

Cell adhesion mediated by the interaction between integrin ₄₁ and VCAM-1 is important in normal physiologic processes and in inflammatory and autoimmune disease. Numerous studies have mapped the ₄₁ binding sites in VCAM-1 that mediate cell adhesion; however, little is known about the regions in VCAM-1 important for regulating soluble binding. In the present study, we demonstrate that 6D VCAM-1 (an alternatively spliced isoform of VCAM-1 lacking Ig-like domain 4) binds ₄₁ with a higher relative affinity than does the full-length form of VCAM-1 containing 7 Ig-like extracellular domains (7D VCAM-1). In indirect binding assays, the EC₅₀ of soluble 6D VCAM-1 binding to ₄₁ on Jurkat cells (in 1 mM MnCl₂) was 2 x 10^–9 M, compared with 7D VCAM-1 at 11 x 10^–9 M. When used in solution to inhibit ₄₁ mediated cell adhesion, the IC₅₀ of 6D VCAM-1 was 13 x 10^–9 M, compared with 7D VCAM-1 measured at 150 x 10^–9 M. Removal of Ig-like domains 4, 5, or 6, or simply substituting Asp³²⁸ in domain 4 of 7D VCAM-1 with alanine, caused increased binding of soluble 7D VCAM-1 to ₄₁. In contrast, cells adhered more avidly to 7D VCAM-1 under shear force, as it induced cell spreading at lower concentrations than did 6D VCAM-1. Finally, soluble 6D VCAM-1 acts as an agonist through ₄₁ by augmenting cell migration and inducing cell aggregation. These results indicate that the domain 4 of VCAM-1 plays a contrasting role when VCAM-1 is presented in solution or as a cell surface-expressed adhesive substrate.

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