c-Jun N-terminal kinase (JNK) signaling: Recent advances and challenges |
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Authors: | Marie A. Bogoyevitch Kevin R.W. NgoeiTeresa T. Zhao Yvonne Y.C. YeapDominic C.H. Ng |
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Affiliation: | Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia |
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Abstract: | c-Jun N-terminal kinases (JNKs), first characterized as stress-activated members of the mitogen-activated protein kinase (MAPK) family, have become a focus of inhibitor screening strategies following studies that have shown their critical roles in the development of a number of diseases, such as diabetes, neurodegeneration and liver disease. We discuss recent advances in the discovery and development of ATP-competitive and ATP-noncompetitive JNK inhibitors. Because understanding the modes of actions of these inhibitors and improving their properties will rely on a better understanding of JNK structure, JNK catalytic mechanisms and substrates, recent advances in these areas of JNK biochemistry are also considered. In addition, the use of JNK gene knockout animals is continuing to reveal in vivo functions for these kinases, with tissue-specific roles now being dissected with tissue-specific knockouts. These latest advances highlight the many challenges now faced, particularly in the directed targeting of the JNK isoforms in specific tissues. |
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Keywords: | Ago, Argonaute DELFIA, Dissociation Enhanced Lathanide Fluoro-Immuno Assay D-JNKI-1, cell-permeable JIP1-derived JNK inhibitory peptide-1 (D-amino acids) ELISA, enzyme-linked immunosorbent assays ERK, extracellular signal-regulated kinase (ERK) FITC, fluorescein-isothiocyanate FRET, Fluorescence Resonance Energy Transfer GSK, glycogen synthase kinase JNKs, c-Jun N-terminal kinases JIP1, JNK-interacting protein-1 L-JNKI-1, cell-permeable JIP1-derived JNK inhibitory peptide-1 (L-amino acids) MAPK, mitogen-activated protein kinase miRNA, microRNA MKK, MAPK kinase Myt1, membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase NMR, nuclear magnetic resonance PDB, Protein DataBase PP2C, protein phosphatase 2C RISC, RNA-induced silencing complex SAPK, stress-activated protein kinase Smac, second mitochondria-derived activator of caspases TAT-TIJP, shorter version of the L-JNKI-1 TAT-linked JIP-based inhibitory peptide XIAP, X-linked inhibitor of apoptosis |
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