{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:00:50Z","timestamp":1780509650180,"version":"3.54.1"},"reference-count":50,"publisher":"American Society for Cell Biology (ASCB)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2004,4]]},"abstract":"<jats:p>Neural cell adhesion molecules (CAMs) are important players during neurogenesis and neurite outgrowth as well as axonal fasciculation and pathfinding. Some of these developmental processes entail the activation of cellular signaling cascades. Pharmacological and genetic evidence indicates that the neurite outgrowth-promoting activity of L1-type CAMs is at least in part mediated by the stimulation of neuronal receptor tyrosine kinases (RTKs), especially FGF and EGF receptors. It has long been suspected that neural CAMs might physically interact with RTKs, but their activation by specific cell adhesion events has not been directly demonstrated. Here we report that gain-of-function conditions of the Drosophila L1-type CAM Neuroglian result in profound sensory axon pathfinding defects in the developing Drosophila wing. This phenotype can be suppressed by decreasing the normal gene dosage of the Drosophila EGF receptor gene. Furthermore, in Drosophila S2 cells, cell adhesion mediated by human L1-CAM results in the specific activation of human EGF tyrosine kinase at cell contact sites and EGF receptors engage in a physical interaction with L1-CAM molecules. Thus L1-type CAMs are able to promote the adhesion-dependent activation of EGF receptor signaling in vitro and in vivo.<\/jats:p>","DOI":"10.1091\/mbc.e03-05-0333","type":"journal-article","created":{"date-parts":[[2004,1,13]],"date-time":"2004-01-13T01:24:18Z","timestamp":1073957058000},"page":"2003-2012","source":"Crossref","is-referenced-by-count":76,"title":["Activation of EGF Receptor Kinase by L1-mediated Homophilic Cell Interactions"],"prefix":"10.1091","volume":"15","author":[{"given":"Rafique","family":"Islam","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars V.","family":"Kristiansen","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109"},{"name":"Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez, San Juan de Alicante, 03550 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Romani","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez, San Juan de Alicante, 03550 Spain"},{"name":"MRC Center for Developmental Neurobiology, King's College, London SE1 1UL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Garcia-Alonso","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez, San Juan de Alicante, 03550 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hortsch","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1076","reference":[{"key":"REF1","doi-asserted-by":"crossref","unstructured":"Anderson, D.J., and Blobel, G. (1983). Immunoprecipitation of proteins from cell-free translations.Methods Enzymol.96,111-120.","DOI":"10.1016\/S0076-6879(83)96012-3"},{"key":"REF2","unstructured":"Bieber, A.J. (1994). Analysis of cellular adhesion in cultured cells. In:Drosophila melanogaster: Practical Uses in Cell Biology, Vol.44, ed. L. Goldstein and E. Fyrberg, San Diego: Academic Press, 683-696."},{"key":"REF3","doi-asserted-by":"crossref","unstructured":"Brand, A.H., and Perrimon, N. (1993). Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.Development118,401-415.","DOI":"10.1242\/dev.118.2.401"},{"key":"REF4","doi-asserted-by":"crossref","unstructured":"Bunch, T.A., Grinblat, Y., and Goldstein, L.S.B. (1988). Characterization and use of theDrosophilametallothionein promoter in culturedDrosophila melanogastercells.Nucleic Acids Res.16,1043-1061.","DOI":"10.1093\/nar\/16.3.1043"},{"key":"REF5","doi-asserted-by":"crossref","unstructured":"Cavallaro, U., Niedermeyer, J., Fuxa, M., and Christofori, G. (2001). N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling.Nat. Cell Biol.3,650-657.","DOI":"10.1038\/35083041"},{"key":"REF6","doi-asserted-by":"crossref","unstructured":"Chen, L., Ong, B., and Bennett, V. (2001). LAD-1, theCaenorhabditis elegansL1CAM homologue, participants in embryonic and gonadal morphogenesis and is a substrate for fibroblast growth factor receptor pathway-dependent phosphotyrosine-based signalling.J. Cell. Biol.154,841-856.","DOI":"10.1083\/jcb.200009004"},{"key":"REF7","doi-asserted-by":"crossref","unstructured":"Doherty, P., Williams, G., and Williams, E.J. (2000). CAMs and axonal growth: a critical evaluation of the role of calcium and the MAPK cascade.Mol. Cell. Neurosci.16,283-295.","DOI":"10.1006\/mcne.2000.0907"},{"key":"REF8","doi-asserted-by":"crossref","unstructured":"Dominguez, M., Wasserman, J.D., and Freeman, M. (1998). Multiple functions of the EGF receptor inDrosophilaeye development.Curr. Biol.8,1039-1048.","DOI":"10.1016\/S0960-9822(98)70441-5"},{"key":"REF9","doi-asserted-by":"crossref","unstructured":"Dubreuil, R.R., MacVicar, G., Dissanayake, S., Liu, C., Homer, D., and Hortsch, M. (1996). Neuroglian-mediated cell adhesion induces assembly of the membrane skeleton at cell contact sites.J. Cell Biol.133,647-655.","DOI":"10.1083\/jcb.133.3.647"},{"key":"REF10","doi-asserted-by":"crossref","unstructured":"Dumstrei, K., Nassif, C., Abboud, G., Aryai, A., and Hartenstein, V. (1998). EGFR signaling is required for the differentiation and maintenance of neural progenitors along the dorsal midline of theDrosophilaembryonic head.Development125,3417-3426.","DOI":"10.1242\/dev.125.17.3417"},{"key":"REF11","doi-asserted-by":"crossref","unstructured":"Elkins, T., Hortsch, M., Bieber, A.J., Snow, P.M., and Goodman, C.S. (1990).Drosophilafasciclin I is a novel homophilic adhesion molecule that along with fasciclin III can mediate cell sorting.J. Cell Biol.110,1825-1832.","DOI":"10.1083\/jcb.110.5.1825"},{"key":"REF12","doi-asserted-by":"crossref","unstructured":"Garcia-Alonso, L., Romani, S., and Jimenez, F. (2000). The EGF and FGF receptors mediate neuroglian function to control growth cone decisions during sensory axon guidance inDrosophila.Neuron28,741-752.","DOI":"10.1016\/S0896-6273(00)00150-1"},{"key":"REF13","doi-asserted-by":"crossref","unstructured":"Giangrande, A. (1994). Glia in the fly wing are clonally related to epithelial cells and use the nerve as pathways for migration.Development120,523-534.","DOI":"10.1242\/dev.120.3.523"},{"key":"REF14","doi-asserted-by":"crossref","unstructured":"Hall, S.G., and Bieber, A.J. (1997). Mutations in theDrosophilaneuroglian cell adhesion molecule affect motor neuron pathfinding and peripheral nervous system patterning.J. Neurobiol.32,325-340.","DOI":"10.1002\/(SICI)1097-4695(199703)32:3<325::AID-NEU6>3.0.CO;2-9"},{"key":"REF15","unstructured":"Hertweck, H. (1931). Anatomie und Variabilit\u00e4t des Nervensystems und der Sinnesorgane vonDrosophila melanogaster(Meigen).Zeitschr. wiss. Zool.139,559-663."},{"key":"REF16","doi-asserted-by":"crossref","unstructured":"Hortsch, M. (2000). Structural and functional evolution of the L1-family: Are four adhesion molecules better than one?Mol. Cell. Neurosci.15,1-10.","DOI":"10.1006\/mcne.1999.0809"},{"key":"REF17","doi-asserted-by":"crossref","unstructured":"Hortsch, M., Avossa, D., and Meyer, D.I. (1985). A structural and functional analysis of the docking protein. Characterization of active domains by proteolysis and specific antibodies.J. Biol. Chem.260,9137-9145.","DOI":"10.1016\/S0021-9258(17)39341-9"},{"key":"REF18","doi-asserted-by":"crossref","unstructured":"Hortsch, M., Bieber, A.J., Patel, N.H., and Goodman, C.S. (1990). Differential splicing generates a nervous system-specific form ofDrosophilaneuroglian.Neuron4,697-709.","DOI":"10.1016\/0896-6273(90)90196-M"},{"key":"REF19","doi-asserted-by":"crossref","unstructured":"Hortsch, M., and Goodman, C.S. (1990).Drosophilafasciclin I, a neural cell adhesion molecule, has a phosphatidylinositol lipid membrane anchor that is developmentally regulated.J. Biol. Chem.265,15104-15109.","DOI":"10.1016\/S0021-9258(18)77229-3"},{"key":"REF20","doi-asserted-by":"crossref","unstructured":"Hortsch, M., O'Shea, K.S., Zhao, G., Kim, F., Vallejo, Y., and Dubreuil, R.R. (1998). A conserved role for L1 as a transmembrane link between neuronal adhesion and membrane cytoskeleton assembly.Cell Adhes. Commun.5,61-73.","DOI":"10.3109\/15419069809005599"},{"key":"REF21","doi-asserted-by":"crossref","unstructured":"Hortsch, M., Schlessinger, J., Gootwine, E., and Webb, C.G. (1983). Appearance of functional EGF receptor kinase during rodent embryogenesis.EMBO J.2,1937-1941.","DOI":"10.1002\/j.1460-2075.1983.tb01682.x"},{"key":"REF22","doi-asserted-by":"crossref","unstructured":"Imbert, V., Peyron, J.F., Farahi Far, D., Mari, B., Auberger, P., and Rossi, B. (1994). Induction of tyrosine phosphorylation and T-cell activation by vanadate peroxide, an inhibitor of protein tyrosine phosphatases.Biochem. J.297,163-173.","DOI":"10.1042\/bj2970163"},{"key":"REF23","doi-asserted-by":"crossref","unstructured":"Islam, R., Wei, S.Y., Chiu, W.H., Hortsch, M., and Hsu, J.C. (2003). Neuroglian activates Echinoid to antagonize theDrosophilaEGF receptor signaling pathway.Development130,2051-2059.","DOI":"10.1242\/dev.00415"},{"key":"REF24","doi-asserted-by":"crossref","unstructured":"Kamiguchi, H., and Lemmon, V. (2000). IgCAMs: bidirectional signals underlying neurite growth.Curr. Opin. Cell Biol.12,598-605.","DOI":"10.1016\/S0955-0674(00)00138-1"},{"key":"REF25","doi-asserted-by":"crossref","unstructured":"Kenwrick, S., Watkins, A., and Angelis, E.D. (2000). Neural cell recognition molecule L1,relating biological complexity to human disease mutations.Hum. Mol. Genet.9,879-886.","DOI":"10.1093\/hmg\/9.6.879"},{"key":"REF26","doi-asserted-by":"crossref","unstructured":"Kolkova, K., Novitskaya, V., Pedersen, N., Berezin, V., and Bock, E. (2000). Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway.J. Neurosci.20,2238-2246.","DOI":"10.1523\/JNEUROSCI.20-06-02238.2000"},{"key":"REF27","doi-asserted-by":"crossref","unstructured":"Kornblum, H.I., Raymon, H.K., Morrison, R.S., Cavanaugh, K.P., Bradshaw, R.A., and Leslie, F.M. (1990). Epidermal growth factor and basic fibroblast growth factor: effects on an overlapping population of neocortical neuronsin vitro.Brain Res.535,255-263.","DOI":"10.1016\/0006-8993(90)91608-J"},{"key":"REF28","doi-asserted-by":"crossref","unstructured":"Kumar, J.P., Tio, M., Hsiung, F., Akopyan, S., Gabay, L., Seger, R., Shilo, B.Z., and Moses, K. (1998). Dissecting the roles of theDrosophilaEGF receptor in eye development and MAP kinase activation.Development125,3875-3885.","DOI":"10.1242\/dev.125.19.3875"},{"key":"REF29","doi-asserted-by":"crossref","unstructured":"Lage, P., Jan, Y.N., and Jarman, A.P. (1997). Requirement for EGF receptor signalling in neural recruitment during formation ofDrosophilachordotonal sense organ clusters.Curr. Biol.7,166-175.","DOI":"10.1016\/S0960-9822(97)70087-3"},{"key":"REF30","doi-asserted-by":"crossref","unstructured":"Lemmon, V., Farr, K.L., and Lagenaur, C. (1989). L1-mediated axon outgrowth occurs via a homophilic binding mechanism.Neuron2,1597-1603.","DOI":"10.1016\/0896-6273(89)90048-2"},{"key":"REF31","doi-asserted-by":"crossref","unstructured":"Malhotra, J.D., Tsiotra, P., Karagogeos, D., and Hortsch, M. (1998). Cis-activation of L1-mediated ankyrin recruitment by TAG-1 homophilic cell adhesion.J. Biol. Chem.273,33354-33359.","DOI":"10.1074\/jbc.273.50.33354"},{"key":"REF32","doi-asserted-by":"crossref","unstructured":"Margolis, B., Rhee, S.G., Felder, S., Mervic, M., Lyall, R., Levitzki, A., Ullrich, A., Zilberstein, A., and Schlessinger, J. (1989). EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling.Cell57,1101-1107.","DOI":"10.1016\/0092-8674(89)90047-0"},{"key":"REF33","doi-asserted-by":"crossref","unstructured":"Meisenhelder, J., Suh, P.G., Rhee, S.G., and Hunter, T. (1989). Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinasesin vivoandin vitro.Cell57,1109-1122.","DOI":"10.1016\/0092-8674(89)90048-2"},{"key":"REF34","doi-asserted-by":"crossref","unstructured":"Morrison, R.S., Keating, R.F., and Moskal, J.R. (1988). Basic fibroblast growth factor and epidermal growth factor exert differential trophic effects on CNS neurons.J. Neurosci. Res.21,71-79.","DOI":"10.1002\/jnr.490210111"},{"key":"REF35","doi-asserted-by":"crossref","unstructured":"Murray, M.A., Schubiger, M., and Palka, J. (1984). Neuron differentiation and axon growth in the developing wing ofDrosophila melanogaster.Dev. Biol.104,259-273.","DOI":"10.1016\/0012-1606(84)90082-4"},{"key":"REF36","doi-asserted-by":"crossref","unstructured":"Niethammer, P., Delling, M., Sytnyk, V., Dityatev, A., Fukami, K., and Schachner, M. (2002). Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis.J. Cell Biol.157,521-532.","DOI":"10.1083\/jcb.200109059"},{"key":"REF37","doi-asserted-by":"crossref","unstructured":"Okabe, M., and Okano, H. (1997). Two-step induction of chordotonal organ precursors inDrosophilaembryogenesis.Development124,1045-1053.","DOI":"10.1242\/dev.124.5.1045"},{"key":"REF38","unstructured":"Panicker, A.K., Buhusi, M., Thelen, K., and Maness, P.F. (2003). Cellular signalling mechanisms of neural cell adhesion molecules.Front. Biosci.8,D900-911."},{"key":"REF39","doi-asserted-by":"crossref","unstructured":"Plotnikov, A.N., Schlessinger, J., Hubbard, S.R., and Mohammadi, M. (1999). Structural basis for FGF receptor dimerization and activation.Cell98,641-650.","DOI":"10.1016\/S0092-8674(00)80051-3"},{"key":"REF40","doi-asserted-by":"crossref","unstructured":"Price, J.V., Clifford, R.J., and Sch\u00fcpbach, T. (1989). The maternal ventralizing locustorpedois allelic to faint little ball, an embryonic lethal, and encodes theDrosophilaEGF receptor homolog.Cell56,1085-1092.","DOI":"10.1016\/0092-8674(89)90641-7"},{"key":"REF41","doi-asserted-by":"crossref","unstructured":"Saffell, J.L., Williams, E.J., Mason, I.J., Walsh, F.S., and Doherty, P. (1997). Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs.Neuron18,231-242.","DOI":"10.1016\/S0896-6273(00)80264-0"},{"key":"REF42","doi-asserted-by":"crossref","unstructured":"Schaefer, A.W., Kamiguchi, H., Wong, E.V., Beach, C.M., Landreth, G., and Lemmon, V. (1999). Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization.J. Biol. Chem.274,37965-37973.","DOI":"10.1074\/jbc.274.53.37965"},{"key":"REF43","doi-asserted-by":"crossref","unstructured":"Schmid, R.S., Pruitt, W.M., and Maness, P.F. (2000). A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis.J. Neurosci.20,4177-4188.","DOI":"10.1523\/JNEUROSCI.20-11-04177.2000"},{"key":"REF44","doi-asserted-by":"crossref","unstructured":"Schweitzer, R., Shaharabany, M., Seger, R., and Shilo, B.Z. (1995). Secreted Spitz triggers the DER signaling pathway and is a limiting component in embryonic ventral ectoderm determination.Genes Dev.9,1518-1529.","DOI":"10.1101\/gad.9.12.1518"},{"key":"REF45","doi-asserted-by":"crossref","unstructured":"Shapiro, L., Fannon, A.M., Kwong, P.D., Thompson, A., Lehmann, M.S., Grubel, G., Legrand, J.F., Als-Nielsen, J., Colman, D.R., and Hendrickson, W.A. (1995). Structural basis of cell-cell adhesion by cadherins.Nature374,327-337.","DOI":"10.1038\/374327a0"},{"key":"REF46","doi-asserted-by":"crossref","unstructured":"Wahl, M.I., Daniel, T.O., and Carpenter, G. (1988). Antiphosphotyrosine recovery of phospholipase C activity after EGF treatment of A-431 cells.Science241,968-970.","DOI":"10.1126\/science.2457254"},{"key":"REF47","doi-asserted-by":"crossref","unstructured":"Weiss, A., and Schlessinger, J. (1998). Switching signals on or off by receptor dimerization.Cell94,277-280.","DOI":"10.1016\/S0092-8674(00)81469-5"},{"key":"REF48","doi-asserted-by":"crossref","unstructured":"Williams, E.J., Furness, J., Walsh, F.S., and Doherty, P. (1994). Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin.Neuron13,583-594.","DOI":"10.1016\/0896-6273(94)90027-2"},{"key":"REF49","doi-asserted-by":"crossref","unstructured":"Yamada, M., Ikeuchi, T., and Hatanaka, H. (1997). The neurotrophic action and signalling of epidermal growth factor.Prog. Neurobiol.51,19-37.","DOI":"10.1016\/S0301-0082(96)00046-9"},{"key":"REF50","doi-asserted-by":"crossref","unstructured":"Zak, N.B., Wides, R.J., Schejter, E.D., Raz, E., and Shilo, B.Z. (1990). Localization of the DER\/flb protein in embryos: implications on the faint little ball lethal phenotype.Development109,865-874.","DOI":"10.1242\/dev.109.4.865"}],"container-title":["Molecular Biology of the Cell"],"original-title":[],"language":"en","deposited":{"date-parts":[[2021,6,13]],"date-time":"2021-06-13T21:29:34Z","timestamp":1623619774000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.molbiolcell.org\/doi\/10.1091\/mbc.e03-05-0333"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,4]]},"references-count":50,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2004,4]]}},"alternative-id":["10.1091\/mbc.e03-05-0333"],"URL":"https:\/\/doi.org\/10.1091\/mbc.e03-05-0333","relation":{},"ISSN":["1059-1524","1939-4586"],"issn-type":[{"value":"1059-1524","type":"print"},{"value":"1939-4586","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,4]]}}}