News and Publications

Structure, Function, and Posttranslational Cleavage of the L1 Cell Adhesion Molecule

A.M.P. Montgomery, N. Nayeem, S. Silletti, B. Felding-Habermann

Early studies established L1 as a neural cell adhesion molecule that participates in a variety of neural developmental and regenerative processes. These studies also indicated that L1 can support cell-cell interactions by virtue of homophilic L1-L1 binding. Despite its designation as a neural cell adhesion molecule, we recently showed that L1 can also be expressed by vascular cells and cells of lymphoid or myelomonocytic origin. Furthermore, we found that isolated L1 can also serve as a heterophilic ligand for multiple integrins that depend on the arginine--glycine--aspartic acid sequence of amino acids.

We have now shown that L1 can function as a recognition molecule for both platelets and endothelial cells. The interaction between L1 and endothelial cells is mediated by ₅ß₁, _vß₃, and _vß₁, whereas platelets adhere to L1 via ₅ß₁ and _IIbß₃. All these interactions depend on recognition of a single arginine--glycine--aspartic acid motif present in the sixth immunoglobulin-like domain of L1. Without prior cellular activation, the interaction between L1 and ₅ß₁ may require recognition of an additional accessory binding motif located in a proximal fibronectin-like type III repeat. Because L1 can interact with multiple vascular or platelet integrins, our evidence of de novo or increased expression of L1 on endothelium in certain vascular autoimmune diseases is important. We are investigating whether L1 expressed by activated or damaged endothelium can contribute to the recruitment of immune cells and therefore the immunopathogenesis of these diseases.

Posttranslational cleavage of L1 is thought to be an important mechanism for regulating the expression and function of this cell adhesion molecule in vivo. However, little is known of the proteolytic pathways responsible for this cleavage. We recently obtained evidence that the plasminogen activator/plasmin(ogen) system may be a pathway for regulating expression and function of L1. Addition of plasmin to cultured cells caused a dose-dependent loss of immunoreactivity of L1 on the cell surface and the simultaneous appearance of soluble L1 products. Cleavage of L1 also occurred after the addition of plasminogen to cells expressing urokinase and the receptor for this activator.

One product of plasmin-catalyzed cleavage is a large amino-terminal fragment of L1 that has been described as a natural posttranslational cleavage product in neural tissues. Generation of this fragment is due to cleavage adjacent to a conserved dibasic sequence in the third fibronectin-like domain of L1. We found that plasmin disrupted homophilic L1-L1 binding required for cell adhesion and homotypic aggregation. We are investigating the pathophysiologic function of L1 cleavage products, including their role in modulating angiogenesis and immune and vascular cell interactions.

PUBLICATIONS

Brooks, P.C., Montgomery, A.M.P., Cheresh, D.A. Use of the avian model for studying angiogenesis. Methods Mol. Biol., in press.

Felding-Habermann B., Silletti, S., Mei, F., Siu, C.-H., Yip, P., Brooks, P.C., Cheresh, D.A., O'Toole, T.E., Ginsberg, M.H., Montgomery, A.M.P. A single immunoglobulin-like domain of the human neural cell adhesion molecule L1 supports adhesion by multiple vascular and platelet integrins. J. Cell Biol. 139:1, 1997.

Yip, P.M., Zhao, X., Montgomery, A.M.P., Siu, C.-H. The Arg-Gly-Asp motif in the cell adhesion molecule L1 promotes neurite outgrowth via interaction with the _vß₃ integrin. Mol. Biol. Cell 9:277, 1988.