Dimeric Versions of Two Short N-cadherin Binding Motifs (HAVDI and INPISG) Function as N-cadherin Agonists*

N-cadherin is a member of the classical cadherin family of homophilic binding molecules. Peptide competition studies have identified the HAVDI and INPISGQ sequences as functional binding motifs in extracellular domain 1 (ECD1) of N-cadherin. Whereas monomeric versions of these motifs function as specific N-cadherin antagonists, we now show that cyclic peptides containing a tandem repeat of the individual motifs function as N-cadherin agonists. In this context, when presented to neurons as soluble molecules, the dimeric versions of the motifs stimulate neurite outgrowth in a similar manner to native N-cadherin. The response to the dimeric agonist peptides was inhibited by monomeric versions of the same motif and also by recombinant N-cadherin ECD1 protein. The responses were also inhibited by antibodies to a fibroblast growth factor receptor (FGFR) binding motif in ECD4 of N-cadherin and by a specific FGFR antagonist (PD17304). These data suggest that the peptides function by binding to and clustering N-cadherin in neurons and thereby activating an N-cadherin/FGFR signaling cascade. The novel agonists will be invaluable for dissecting out those cadherin functions that rely on signaling as opposed to adhesion and clearly have the potential to be developed as therapeutic agents for the promotion of cell survival and axonal regeneration.