L1 Signalling

In the late 1980's studies from M. Schachner's group indicated that L1 was not just an adhesion molecule but could also influence signaling pathways. Our own studies of growth cone behavior on different adhesion molecules lead us to similar conclusions. We decided to start by characterizing L1 associated kinases. We found that the MAP kinase cascade was a significant target of L1 signalling. Not only are raf, ERK and p90rsk associated with L1 but ERK and p90rsk can phosphorylate L1 at site likely to regulate interactions with the cytoskeleton and trafficking machinery. Furthermore, a peptide corresponding to the p90rsk phosphorylation site inhibits neurite growth on an L1 substrate but not on laminin, indicating this site is important for neurite growth. We also found that inhibition of clathrin mediated internalization blocked activation of the MAP kinase pathway by L1. A second pathway involves casein kinase II. This kinase is associated with L1 and phosphorylates L1 at a site likely to regulate L1 internalization. We have identified other phosphorylation sites in L1 and are working to identify the associated kinases and the regulatory functions of these sites.

A series of experiments by Andy Schaefer and Y. Kamei, using a monoclonal antibody called 74-5H7, have indicated that dephosphorylation of L1 is also regulated by L1 mediated adhesion. This seems to peak at about 60 min after cell contact. We are working to study how this happens and what phosphatase is involved. This was described in a recent paper in J. Cell Biology (157: 1223-1232, 2002)

Several investiagators have shown that L1 subfamily CAMs interact with GPI-linked CAMs like axonin-1 and F3/F1/contactin. Also, signalling from L1 and GPI-linked CAMs have been liked to src. Since the GPI-linked CAMs and src-family kinases are found in lipid rafts we have initiated a project in colloboration with K. Watanabe and Y. Takeda at Tokyo Metropolitian Institute of Gerentology to explore L1 signalling in rafts.

Related Publications

Wong, E.V., Schaefer, A.W., Landreth, G., Lemmon, V. Casein kinase II phosphorylates the neural cell adhesion molecule L1, J. Neurochem., 66:779-786, 1996

Wong, E.V., Schaefer, A.W., Landreth, G. and Lemmon, V. Involvement of p90rsk in neurite outgrowth mediated by the cell adhesion molecule L1. J. Biol. Chem. 271:18217-18233, 1996.

Schaefer, A.W., Kamiguchi, H., Wong, E.V., Beach, C.M., Landreth, G., and Lemmon, V. Activation of the MAPK Signal Cascade by the Neural Cell Adhesion Molecule L1 Requires L1 Internalization. J. Biol. Chem. 274:37965-37973., 1999.

Kamiguchi, H., and Lemmon, V. IgCAMs: Bi-directional signals underlying neurite growth. Current Opinion in Cell Biology, 12:598-605, 2000.

A.W. Schaefer, Y. Kamei, H. Kamiguchi, E.V. Wong, I. Rapoport, T. Kirchhausen, C.M. Beach, G. Landreth, S.K. Lemmon, V. Lemmon. L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1. J. Cell Biology, 157: 1223–1232, 2002





Copyright 2003, Dr. Vance Lemmon and Dr. John Bixby. All Rights Reserved