title: The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7.
abstract: The functions of mitogen-activated protein kinases (MKKs) 4 and 7 are typically associated with the c-Jun N-terminal kinase (JNK) signaling pathway. Both MKKs synergistically phosphorylate different JNK isoforms and are therefore involved in numerous physiological (e.g. differentiation and proliferation) and pathological (e.g. apoptosis and tumorigenesis) processes. MKK4 and MKK7 share similar molecular characteristics as well as several upstream activators and scaffold proteins. However, their functions are non-redundant and determined by different stimuli, biochemical interactions and differential tissue distribution. The central question is how two MKKs regulate or affect the multiple actions of their JNK substrates. Similar to JNKs, MKK4 and MKK7 can simultaneously exert divergent functions in different cellular compartments and signalosomes. It is also important to realize that the MKK effects are splice variant-specific. The present review not only summarizes the various modes of MKK4 and MKK7 activation and activity, but also their functions. We also extensively describe their impact on JNK signaling, their molecular interactions resulting in the formation of context-specific signalosomes and the functional consequences of JNK deficiency.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105 Kiel, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Haeusgen
authors.forename: Thomas
authors.initials: T
authors.lastname: Herdegen
authors.forename: Vicki
authors.initials: V
authors.lastname: Waetzig
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism*; D020935:MAP Kinase Signaling System
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7