J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/12/1567/15 $2.00
Volume 139, Number 6, December 15, 1997 1567-1581

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, Fang Mei, Chi-Hung Siu,^§ Paul M. Yip,^§ Peter C. Brooks, David A. Cheresh, Timothy E. O'Toole, Mark H. Ginsberg, and Anthony M.P. Montgomery

^* Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis; Department of Molecular and Experimental Medicine,  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 _v3, _v1, ₅₁, and _IIb3. The interaction between L1-Ig6 and _IIb3 was found to support the rapid attachment of activated human platelets, whereas a corresponding interaction with _v3 and _v1 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 _v3, _v1, ₅₁, and _IIb3. 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 ₅₁ and _v1 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 _v3 or active _IIb3 > _v1 > ₅₁. 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Maddaluno, L., Verbrugge, S. E., Martinoli, C., Matteoli, G., Chiavelli, A., Zeng, Y., Williams, E. D., Rescigno, M., Cavallaro, U. (2009). The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells. JEM 206: 623-635 [Abstract] [Full Text]  
• Finas, D., Huszar, M., Agic, A., Dogan, S., Kiefel, H., Riedle, S., Gast, D., Marcovich, R., Noack, F., Altevogt, P., Fogel, M., Hornung, D. (2008). L1 cell adhesion molecule (L1CAM) as a pathogenetic factor in endometriosis. Hum Reprod 23: 1053-1062 [Abstract] [Full Text]  
• Buhusi, M., Schlatter, M. C., Demyanenko, G. P., Thresher, R., Maness, P. F. (2008). L1 Interaction with Ankyrin Regulates Mediolateral Topography in the Retinocollicular Projection. J. Neurosci. 28: 177-188 [Abstract] [Full Text]  
• Zhuang, S., Kelo, L., Nardi, J. B., Kanost, M. R. (2007). An Integrin-Tetraspanin Interaction Required for Cellular Innate Immune Responses of an Insect, Manduca sexta. J. Biol. Chem. 282: 22563-22572 [Abstract] [Full Text]  
• Anderson, E., Maday, S., Sfakianos, J., Hull, M., Winckler, B., Sheff, D., Folsch, H., Mellman, I. (2005). Transcytosis of NgCAM in epithelial cells reflects differential signal recognition on the endocytic and secretory pathways. JCB 170: 595-605 [Abstract] [Full Text]  
• Gutwein, P., Stoeck, A., Riedle, S., Gast, D., Runz, S., Condon, T. P., Marme, A., Phong, M.-C., Linderkamp, O., Skorokhod, A., Altevogt, P. (2005). Cleavage of L1 in Exosomes and Apoptotic Membrane Vesicles Released from Ovarian Carcinoma Cells. Clin. Cancer Res. 11: 2492-2501 [Abstract] [Full Text]  
• Cheng, L., Itoh, K., Lemmon, V. (2005). L1-Mediated Branching Is Regulated by Two Ezrin-Radixin-Moesin (ERM)-Binding Sites, the RSLE Region and a Novel Juxtamembrane ERM-Binding Region. J. Neurosci. 25: 395-403 [Abstract] [Full Text]  
• Buhusi, M., Midkiff, B. R., Gates, A. M., Richter, M., Schachner, M., Maness, P. F. (2003). Close Homolog of L1 Is an Enhancer of Integrin-mediated Cell Migration. J. Biol. Chem. 278: 25024-25031 [Abstract] [Full Text]  
• Prevost, N., Woulfe, D., Tanaka, T., Brass, L. F. (2002). Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred. Proc. Natl. Acad. Sci. USA 99: 9219-9224 [Abstract] [Full Text]  
• Thelen, K., Kedar, V., Panicker, A. K., Schmid, R.-S., Midkiff, B. R., Maness, P. F. (2002). The Neural Cell Adhesion Molecule L1 Potentiates Integrin-Dependent Cell Migration to Extracellular Matrix Proteins. J. Neurosci. 22: 4918-4931 [Abstract] [Full Text]  
• De Angelis, E., Watkins, A., Schafer, M., Brummendorf, T., Kenwrick, S., Sakaki, Y., Ikemura, T. (2002). Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. Hum Mol Genet 11: 1-12 [Abstract] [Full Text]  
• Kamiguchi, H., Yoshihara, F. (2001). The Role of Endocytic L1 Trafficking in Polarized Adhesion and Migration of Nerve Growth Cones. J. Neurosci. 21: 9194-9203 [Abstract] [Full Text]  
• Mechtersheimer, S., Gutwein, P., Agmon-Levin, N., Stoeck, A., Oleszewski, M., Riedle, S., Postina, R., Fahrenholz, F., Fogel, M., Lemmon, V., Altevogt, P. (2001). Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. JCB 155: 661-674 [Abstract] [Full Text]  
• Voura, E. B., Ramjeesingh, R. A., Montgomery, A. M.P., Siu, C.-H. (2001). Involvement of Integrin alpha vbeta 3 and Cell Adhesion Molecule L1 in Transendothelial Migration of Melanoma Cells. Mol. Biol. Cell 12: 2699-2710 [Abstract] [Full Text]  
• McCarty, O. J. T., Mousa, S. A., Bray, P. F., Konstantopoulos, K. (2000). Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood 96: 1789-1797 [Abstract] [Full Text]  
• Moulding, H. D., Martuza, R. L., Rabkin, S. D. (2000). Clinical Mutations in the L1 Neural Cell Adhesion Molecule Affect Cell-Surface Expression. J. Neurosci. 20: 5696-5702 [Abstract] [Full Text]  
• Silletti, S., Mei, F., Sheppard, D., Montgomery, A. M.P. (2000). Plasmin-sensitive Dibasic Sequences in the Third Fibronectin-like Domain of L1-Cell Adhesion Molecule (CAM) Facilitate Homomultimerization and Concomitant Integrin Recruitment. JCB 149: 1485-1502 [Abstract] [Full Text]  
• Kenwrick, S., Watkins, A., Angelis, E. D. (2000). Neural cell recognition molecule L1: relating biological complexity to human disease mutations. Hum Mol Genet 9: 879-886 [Abstract] [Full Text]  
• Oleszewski, M., Beer, S., Katich, S., Geiger, C., Zeller, Y., Rauch, U., Altevogt, P. (1999). Integrin and Neurocan Binding to L1 Involves Distinct Ig Domains. J. Biol. Chem. 274: 24602-24610 [Abstract] [Full Text]  
• Nayeem, N, Silletti, S, Yang, X, Lemmon, V., Reisfeld, R., Stallcup, W., Montgomery, A. (1999). A potential role for the plasmin(ogen) system in the posttranslational cleavage of the neural cell adhesion molecule L1. J. Cell Sci. 112: 4739-4749 [Abstract]  
• Beer, S, Oleszewski, M, Gutwein, P, Geiger, C, Altevogt, P (1999). Metalloproteinase-mediated release of the ectodomain of L1 adhesion molecule. J. Cell Sci. 112: 2667-2675 [Abstract]  
• Nath, D, Slocombe, P., Stephens, P., Warn, A, Hutchinson, G., Yamada, K., Docherty, A., Murphy, G (1999). Interaction of metargidin (ADAM-15) with alphavbeta3 and alpha5beta1 integrins on different haemopoietic cells. J. Cell Sci. 112: 579-587 [Abstract]  
• Weerasinghe, D., McHugh, K. P., Ross, F. P., Brown, E. J., Gisler, R. H., Imhof, B. A. (1998). A Role for the alpha vbeta 3 Integrin in the Transmigration of Monocytes. JCB 142: 595-607 [Abstract] [Full Text]  
• Aplin, A. E., Howe, A., Alahari, S. K., Juliano, R. L. (1998). Signal Transduction and Signal Modulation by Cell Adhesion Receptors: The Role of Integrins, Cadherins, Immunoglobulin-Cell Adhesion Molecules, and Selectins. Pharmacol. Rev. 50: 197-264 [Abstract] [Full Text]  
• Long, K. E., Asou, H., Snider, M. D., Lemmon, V. (2001). The Role of Endocytosis in Regulating L1-mediated Adhesion. J. Biol. Chem. 276: 1285-1290 [Abstract] [Full Text]  
• Shikano, S., Bonkobara, M., Zukas, P. K., Ariizumi, K. (2001). Molecular Cloning of a Dendritic Cell-associated Transmembrane Protein, DC-HIL, That Promotes RGD-dependent Adhesion of Endothelial Cells through Recognition of Heparan Sulfate Proteoglycans. J. Biol. Chem. 276: 8125-8134 [Abstract] [Full Text]  
• Fujimoto, I., Bruses, J. L., Rutishauser, U. (2001). Regulation of Cell Adhesion by Polysialic Acid. EFFECTS ON CADHERIN, IMMUNOGLOBULIN CELL ADHESION MOLECULE, AND INTEGRIN FUNCTION AND INDEPENDENCE FROM NEURAL CELL ADHESION MOLECULE BINDING OR SIGNALING ACTIVITY. J. Biol. Chem. 276: 31745-31751 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents