A single immunoglobulin-like domain of the human neural cell adhesion molecule L1 supports adhesion by multiple vascular and platelet integrins

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(v) beta(3), alpha(v) beta(1), alpha(5) beta(1), and alpha(II)beta(3). The interaction between L1-Ig6 and alpha(IIb)beta(3), was found to support the rapid attachment of activated human platelets, whereas a corresponding interaction with alpha(v) beta(3) and alpha(v) beta(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 alpha(v) beta(3), alpha(v) beta(1), alpha(5) beta(1), and alpha(IIb)beta(3). Whereas beta(3) integrin binding to L1-Ig6 was evident in the presence of either Ca2+, Mg2+, or Mn2+, a corresponding interaction with the beta(1) integrins was only observed in the presence of Mn2+., Furthermore, such Mn2+-dependent binding by alpha(5) beta(1) and alpha(v) beta(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 alpha(v) beta(3) or active alpha(IIb)beta(3) > alpha(v) beta(1) > alpha(5) beta(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.