Mixed lineage kinase-dependent JNK activation is governed by interactions of scaffold protein JIP with MAPK module components

It has been proposed that JNK-interacting proteins (JIP) facilitate mixed l ineage kinase-dependent signal transduction to JNK by aggregating the three components of a JNK module, A new model for the assembly and regulation of these modules is proposed based on several observations. First, artificial ly induced dimerization of dual leucine zipper-bearing kinase (DLK) confirm ed that DLK dimerization is sufficient to induce DLK activation. Secondly, under basal conditions, DLK associated with JIP is held in a monomeric, unp hosphorylated and catalytically inactive state. Thirdly, JNK recruitment to JIP coincided with significantly decreased affinity of JIP and DLK. JNK pr omoted the dimerization, phosphorylation and activation of JIP-associated D LK. Similarly, treatment of cells with okadaic acid inhibited DLK associati on with JIP and resulted in DLK dimerization in the presence of JIP, In sum mary, JIP maintains DLK in a monomeric, unphosphorylated, inactive state. U pon stimulation, JNK-JIP binding affinity increases while JIP-DLK interacti on affinity is attenuated, Dissociation of DLK from JIP results in subseque nt DLK dimerization, autophosphorylation and module activation. Evidence is provided that this model holds for other MLK-dependent JNK modules.