Model depicting regulation of EphB2 clustering. (A) EphB2 cluster populations are heterogeneous and the abundance of monomers, dimers, and multimers (only tetramers are shown) determines the strength of the cellular response. A mixture of monomers and dimers is essentially inactive because dimers have weak signaling output. A mixture of dimers and multimers leads to a physiological response; however, the response gets stronger when all dimers are converted to multimers. (B) C-Terminal modules of EphB2 have a negative regulatory effect on ephrinB2-induced clustering, possibly by recruiting unknown interacting proteins and by steric hindrance. Deletion of these modules relieves this inhibitory effect and enhances EphB2 clustering and signaling.