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* Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis;
Department of Molecular and Experimental Medicine, 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
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
v
3,
v
1,
5
1, and
IIb
3. The interaction between L1-Ig6 and
IIb
3 was found to support the rapid
attachment of activated human platelets, whereas a corresponding interaction with
v
3 and
v
1 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
v
3,
v
1,
5
1, and
IIb
3. Whereas
3
integrin binding to L1-Ig6 was evident in the presence
of either Ca2+, Mg2+, or Mn2+, a corresponding interaction with the
1 integrins was only observed in the
presence of Mn2+. Furthermore, such Mn2+-dependent
binding by
5
1 and
v
1 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
v
3 or active
IIb
3 >
v
1 >
5
1. 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.
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