Direct interaction of the molecular scaffolds POSH and JIP is required for apoptotic activation of JNKs.
A sequential pathway (the JNK pathway) that includes activation of Rac1/Cdc42, mixed lineage kinases, MAP kinase kinases 4 and 7, and JNKs plays a required role in many paradigms of apoptotic cell death. However, the means by which this pathway is assembled and directed toward apoptotic death has been unclear. Here, we report that propagation of the apoptotic JNK pathway requires the cooperative interaction of two molecular scaffolds, POSH and JIPs. POSH (plenty of SH3s) is a multidomain GTP-Rac1-interacting protein that binds and promotes activation of mixed lineage kinases. JIPs are reported to bind MAP kinase kinases 4/7 and JNKs. We find that POSH and JIPs directly associate with one another to form a multiprotein complex, PJAC (POSH-JIP apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for JNK activation and cell death in response to apoptotic stimuli.
Kukekov
Nickolay V
NV
Department of Pathology and Center for Neurobiology and Behavior College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Xu
Zhiheng
Z
Greene
Lloyd A
LA
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D017931:DNA Primers; C490665:Mapk8ip protein, mouse; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C111370:Sh3md2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases