Pathogenic human L1-CAM mutations reduce the adhesion-dependent activation of EGFR
| Autor: | Kakanahalli Nagaraj, Lars V. Kristiansen, Adam Skrzynski, Carlos Castiella, Luis Garcia-Alonso, Michael Hortsch |
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| Rok vydání: | 2009 |
| Předmět: |
Cell signaling
animal structures Gene Expression Neural Cell Adhesion Molecule L1 Biology Nervous System Malformations medicine.disease_cause Cell Line Cell Adhesion Genetics medicine Animals Humans Cell adhesion Molecular Biology Genetics (clinical) Cell Aggregation Neurons Mutation Cell adhesion molecule Articles General Medicine Cell aggregation Cell biology ErbB Receptors Drosophila Neural cell adhesion molecule Signal transduction Tyrosine kinase Signal Transduction |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1460-2083 0964-6906 2001-1628 |
| Popis: | 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. This work supported in part by grants from the National Institutes of Health (R01 NS32130 to M.H.); the National Science Foundation (IBN 0132819 to M.H.); and a GLOBAL Reach Research, Education and Collaboration in Health International faculty seed grant from the University of Michigan (M.H.). Grants from MCYT (SAF2001-1628, SAF2004-06593 to L.G.-A.); and Generalitat Valenciana (PROMETEO-2008-134 to L.G.-A.) supported the work in Spain. |
| Databáze: | OpenAIRE |
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