Mixed lineage kinases (MLKs): a role in dendritic cells, inflammation and immunity?
This review summarizes current knowledge about the mixed lineage kinases (MLKs) and explores their potential role in inflammation and immunity. MLKs were identified initially as signalling molecules in the nervous system. They were also shown to play a role in the cell cycle. Further studies documented three groups of MLKs, and showed that they may be activated via the c-Jun NH(2) terminal kinase (JNK) pathway, and by Rho GTPases. The biochemistry of the MLKs has been investigated in considerable detail. Homodimerization and heterodimerization can occur, and both autophosphorylation and autoinhibition are seen. The interaction between MLKs and JNK interacting protein (JIP) scaffolds, and the resultant effects on mitogen activated protein kinases, have been identified. Clearly, there is some redundancy within the MLK pathway(s), since mice which lack the MLK3 molecule are not abnormal. However, using a combination of biochemical analysis and pharmacological inhibitors, several recent studies in vitro have suggested that MLKs are not only expressed in cells of the immune system (as well as in the nervous system), but also may be implicated selectively in the signalling pathway that follows on toll-like receptor ligation in innate sentinel cells, such as the dendritic cell.
Handley
Matthew E
ME
Department of Immunology and Molecular Pathology, University College London, London, UK.
Rasaiyaah
Jane
J
Chain
Benjamin M
BM
Katz
David R
DR
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051193:Toll-Like Receptors; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases