title: Pathogenic human L1-CAM mutations reduce the adhesion-dependent activation of EGFR.
abstract: L1-cell adhesion molecule (L1-CAM) belongs to a functionally conserved group of neural cell adhesion molecules that are implicated in many aspects of nervous system development. In many neuronal cells the adhesive function of L1-type CAMs induces cellular signaling processes that involves the activation of neuronal tyrosine protein kinases and among other functions regulates axonal growth and guidance. Mutations in the human L1-CAM gene are responsible for a complex neurodevelopmental condition, generally referred to as L1 syndrome. Several pathogenic L1-CAM mutations have been identified in humans that cause L1 syndrome in affected individuals without affecting the level of L1-CAM-mediated homophilic cell adhesion when tested in vitro. In this study, an analysis of two different pathogenic human L1-CAM molecules indicates that although both induce normal L1-CAM-mediated cell aggregation, they are defective in stimulating human epidermal growth factor receptor tyrosine kinase activity in vitro and are unable to rescue L1 loss-of-function conditions in a Drosophila transgenic model in vivo. These results indicate that the L1 syndrome-associated phenotype might involve the disruption of L1-CAM's functions at different levels. Either by reducing or abolishing L1-CAM protein expression, by interfering with L1-CAM's cell surface expression, by reducing L1-CAM's adhesive ability or by impeding further downstream adhesion-dependent signaling processes.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, 48109-2200, USA.
authors.forename: Kakanahalli
authors.initials: K
authors.lastname: Nagaraj
authors.forename: Lars V
authors.initials: LV
authors.lastname: Kristiansen
authors.forename: Adam
authors.initials: A
authors.lastname: Skrzynski
authors.forename: Carlos
authors.initials: C
authors.lastname: Castiella
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia-Alonso
authors.forename: Michael
authors.initials: M
authors.lastname: Hortsch
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002449:Cell Aggregation; D002460:Cell Line; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D066246:ErbB Receptors