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J. Biol. Chem., Vol. 281, Issue 46, 35208-35216, November 17, 2006

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The Fibroblast Growth Factor Receptor Acid Box Is Essential for Interactions with N-Cadherin and All of the Major Isoforms of Neural Cell Adhesion Molecule^*

From the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom

Interactions between the neural cell adhesion molecules NCAM and N-cadherin with the fibroblast growth factor receptor (FGFR) are important for a number of developmental events and have also been implicated in tumor progression. The factors regulating these interactions are not known. We have used co-immunoprecipitation and co-clustering paradigms to show that both adhesion molecules can interact with the 3Ig IIIC isoform of the FGFR1 in a number of cell types. Interestingly, whereas the interaction can be seen over most of the cell surface, it is not seen at points of cell-cell contact where the adhesion molecules accumulate at stable junctions. We also demonstrate for the first time that all of the major isoforms of NCAM can interact with the FGFR. Using deletion mutagenesis we have found that the adhesion molecule/FGFR interaction can withstand the removal of most of any one of the FGFR immunoglobulin-like domains (D1-D3). In contrast, the FGFR interaction with N-cadherin and NCAM (but not FGF) is absolutely dependant on the presence of the acid box motif that can be found in the linker region between D1 and D2. As this motif can be spliced out of all four FGFRs, it suggests that this is one mechanism that can regulate the interaction of the receptor with different ligand classes.

Received for publication, September 7, 2006

^* This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: The Wolfson Centre for Age-Related Diseases, King's College London, Wolfson Wing Hodgkin Bldg., London SE1 1UL, UK. Tel.: 44-207-848-6811; Fax: 44-207-848-6816; E-mail: patrick.doherty{at}kcl.ac.uk.

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