FGFR can be activated by not only FGFs,but also neural cell adhesion molecule (NCAM). NCAM is a homophilic binding glycoprotein mainly expressed on the surface of neurons.NCAM is thoughtl to induce neurite outgrowth via the FGFR signaling pathway. The extracellular part of the FGFR consists of three immunoglobulin-like (Ig) modules, and that of the NCAM consists of five Ig and two fibronectin type III (F3) modules.Recently, the crystal structure of the first three N-terminal NCAM modules has been determined , and based on this structure, a model of the NCAM homophilic binding has been suggested. According to this model, interactions between the Ig1 and Ig2 modules lead to formation of the NCAM cis-dimers on the surface of the same cell. The cis-dimers from two opposing cells can form two kinds of one-dimensional zippers. When combined, the two types of zippers may form a two-dimensional zipper. The extracellular region of the prototypical FGFR consists of three Ig modules of the intermediate subtype . The Ig2 and Ig3 modules mediate binding to FGF and heparin, whereas the Ig1 module has an autoinhibitory function through direct binding to Ig2 . The FGFR site involved in binding to the NCAM has been mapped to the Ig3 module, and the corresponding NCAM site to the F3(2) module . Affinity of interaction between the FGFR Ig23 modules and the F3(12) modules of the NCAM is much higher than affinity of interaction between the single Ig3 and the F3(2) module. Therefore, it seems likely that Ig2 and the F3(1) module also are involved in this interaction. Thus, it is of interest to test whether the FGFR Ig2 module is involved in the FGFRNCAM interaction. The neural cell adhesion molecule (NCAM) plays important roles in neuronal development, regeneration, and synaptic plasticity. NCAM homophilic binding mediates cell adhesion and induces intracellular signals, in which the fibroblast growth factor receptor plays a prominent role. Recent studies on axon guidance in Drosophila suggest that NCAM also regulates the epidermal growth factor receptor (EGFR) (Molecular and Cellular Neuroscience, 28, 2005, 141). A possible interaction between NCAM and EGFR in mammalian cells has not been investigated. The present study demonstrates for the first time a functional interaction between NCAM and EGFR in mammalian cells and investigates the molecular mechanisms underlying this interaction. First, NCAM and EGFR are shown to play opposite roles in neurite outgrowth regulation in cerebellar granular neurons. The data presented indicate that negative regulation of EGFR is one of the mechanisms underlying the neuritogenic effect of NCAM. Second, it is demonstrated that expression of the NCAM-180 isoform induces EGFR down-regulation in transfected cells and promotes EGFR down-regulation induced by EGF stimulation. It is demonstrated that the mechanism underlying this NCAM-180-induced EGFR down-regulation involves increased EGFR ubiquitination and lysosomal EGFR degradation. Furthermore, NCAM-180-mediated EGFR down-regulation requires NCAM homophilic binding and interactions of the cytoplasmic domain of NCAM-180 with intracellular interaction partners, but does not require NCAM-mediated fibroblast growth factor receptor activation. Related Posts: Neural cell adhesion molecule-180-mediated homophilic binding induces epidermal growth factor receptor (EGFR) down-regulation and uncouples the inhibitory function of EGFR in neurite outgrowth. Neural cell adhesion molecule
Please Rate this Article 5 out of 54 out of 53 out of 52 out of 51 out of 5
Not yet Rated
