Abstract

In this study, we show that the neurite outgrowth response stimulated by N-cadherin is inhibited by a recently developed and highly specific fibroblast growth factor receptor (FGFR) antagonist. To test whether the N-cadherin response also requires FGF function, we developed peptide mimetics of the receptor binding sites on FGFs. Most mimetics inhibit the neurite outgrowth response stimulated by FGF in the absence of any effect on the N-cadherin response. The exceptions to this result were two mimetics of a short FGF1 sequence, which has been shown to interact with the region of the FGFR containing the histidine-alanine-valine motif. These peptides inhibited FGF and N-cadherin responses with similar efficacy. The histidine-alanine-valine region of the FGFR has previously been implicated in the N-cadherin response, and a candidate interaction site has been identified in extracellular domain 4 of N-cadherin. We now show that antibodies directed to this site on N-cadherin inhibit the neurite outgrowth response stimulated by N-cadherin, and peptide mimetics of the site inhibit N-cadherin and FGF responses. Thus, we can conclude that N-cadherin contains a novel motility motif in extracellular domain 4, and that peptide mimetics of this motif can interact with the FGFR.

Highlights

  • N-cadherin is a member of the classical cadherin family of transmembrane glycoproteins that mediate cell-to-cell adhesion via a homophilic binding mechanism [1]

  • We show that antibodies directed to this site on N-cadherin inhibit the neurite outgrowth response stimulated by N-cadherin, and peptide mimetics of the site inhibit N-cadherin and FGF responses

  • When cerebellar granule cells are grown over monolayers of 3T3 fibroblasts that express physiological levels of two additional cell adhesion molecules (NCAM and L1) or in the presence of FGF2, a neurite outgrowth response that is similar to the N-cadherin response is found [16, 36]

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Summary

Introduction

N-cadherin is a member of the classical cadherin family of transmembrane glycoproteins that mediate cell-to-cell adhesion via a homophilic binding mechanism [1]. To test whether the N-cadherin response requires FGF function, we developed peptide mimetics of the receptor binding sites on FGFs. Most mimetics inhibit the neurite outgrowth response stimulated by FGF in the absence of any effect on the N-cadherin response.

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