Human Molecular Genetics Advance Access originally published online on July 19, 2009
Human Molecular Genetics 2009 18(20):3822-3831; doi:10.1093/hmg/ddp325
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Pathogenic human L1-CAM mutations reduce the adhesion-dependent activation of EGFR
1 Department of Cell and Developmental Biology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA, 2 The Protein Laboratory, Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark and 3 Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez, 03550 Sant Joan d'Alacant, Spain
* To whom correspondence should be addressed. Tel: +1 7346472720; Fax: +1 7347641166; Email: hortsch{at}umich.edu
Received May 6, 2009; Revised July 8, 2009; Accepted July 16, 2009
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.
Present address: Department of Applied Zoology, Kuvempu University, Shankaraghatta, Shimoga, India.
Present address: Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, DK-2400 Copenhagen, Denmark.