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© The Rockefeller University Press, 0021-9525/1997//1567 $5.00
The Journal of Cell Biology, Volume 139, Number 6, , 1997 1567-1581

Article

A Single Immunoglobulin-like Domain of the Human Neural Cell Adhesion Molecule L1 Supports Adhesion by Multiple Vascular and Platelet Integrins



Brunhilde Felding-Habermann*, Steve Silletti{ddagger}, Fang Mei{ddagger}, Chi-Hung Siu§, Paul M. Yip§, Peter C. Brooks{ddagger}, David A. Cheresh{ddagger}, Timothy E. O'Toole||, Mark H. Ginsberg||, and Anthony M.P. Montgomery{ddagger}

* Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis; Department of Molecular and Experimental Medicine, {ddagger} Department of Immunology, The Scripps Research Institute, La Jolla, California 92037; § Banting and Best Department of Medical Research and Department of Biochemistry, University of Toronto, Ontario, Canada M5G 1L6; and || Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037

The neural cell adhesion molecule L1 has been shown to function as a homophilic ligand in a variety of dynamic neurological processes. Here we demonstrate that the sixth immunoglobulin-like domain of human L1 (L1-Ig6) can function as a heterophilic ligand for multiple members of the integrin superfamily including {alpha}vβ3, {alpha}vβ1, {alpha}5β1, and {alpha}IIbβ3. The interaction between L1-Ig6 and {alpha}IIbβ3 was found to support the rapid attachment of activated human platelets, whereas a corresponding interaction with {alpha}vβ3 and {alpha}vβ1 supported the adhesion of umbilical vein endothelial cells. Mutation of the single Arg-Gly-Asp (RGD) motif in human L1-Ig6 effectively abrogated binding by the aforementioned integrins. A L1 peptide containing this RGD motif and corresponding flanking amino acids (PSITWRGDGRDLQEL) effectively blocked L1 integrin interactions and, as an immobilized ligand, supported adhesion via {alpha}vβ3, {alpha}vβ1, {alpha}5β1, and {alpha}IIbβ3. Whereas β3 integrin binding to L1-Ig6 was evident in the presence of either Ca2+, Mg2+, or Mn2+, a corresponding interaction with the β1 integrins was only observed in the presence of Mn2+. Furthermore, such Mn2+-dependent binding by {alpha}5β1 and {alpha}vβ1 was significantly inhibited by exogenous Ca2+. Our findings suggest that physiological levels of calcium will impose a hierarchy of integrin binding to L1 such that {alpha}vβ3 or active {alpha}IIbβ3 > {alpha}vβ1 > {alpha}5β1. Given that L1 can interact with multiple vascular or platelet integrins it is significant that we also present evidence for de novo L1 expression on blood vessels associated with certain neoplastic or inflammatory diseases. Together these findings suggest an expanded and novel role for L1 in vascular and thrombogenic processes.

Abbreviations used in this paper: CAM, cell adhesion molecule; GST, glutathione-S-transferase; IgSF, immunoglobulin super family; L1-Ig6, sixth immunoglobulin-like domain of human L1; NCAM, neural cell adhesion molecule; NILE, nerve growth factor–inducible, large external protein; NgCAM, neuron–glial CAM; ORF, open reading frame; PGE1, prostaglandin E1; RGD, Arg-Gly-Asp; VNR, vitronectic receptor.

Address all correspondence to Anthony Montgomery, Department of Immunology, R218, The Scripps Research Institute, La Jolla, CA 92037. Tel.: (619) 784-8109. Fax: (619) 784-2708. E-mail: Montg{at}scripps.edu


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