title: Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions.
abstract: The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In vivo mutation of Pro224 to Ile in endogenous p38MAPK significantly reduced its phosphorylation and activity. This resulted in attenuation of p38MAPK signalling, which in turn caused an enhanced apoptosis and sensitivity to a DNA-damaging drug, cisplatin. We further found a reduction in size and number of lesions in homozygous mice carrying the p38MAPK P224I substitution in a K-ras model of lung tumorigenesis. We propose that cyclophilin-dependent isomerisation of p38MAPK is an important novel mechanism in regulating p38MAPK phosphorylation and functions. Thus, inhibition of this process, including with drugs that are in clinical trials, may improve the efficacy of current anti-cancer therapeutic regimes.
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138673, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Brichkina
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138673, Singapore.
authors.forename: N Tm
authors.initials: NT
authors.lastname: Nguyen
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138673, Singapore.
authors.forename: R
authors.initials: R
authors.lastname: Baskar
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138673, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Wee
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138673, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Gunaratne
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138673, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: R C
authors.initials: RC
authors.lastname: Robinson
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), INSERM, U1081-UMR CNRS 7284, University of Nice - Sophia Antipolis, Centre Antoine Lacassagne, Nice, France.
authors.forename: D V
authors.initials: DV
authors.lastname: Bulavin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D021983:Cyclophilins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007536:Isomerism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011392:Proline / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D011392:Proline; D048051:p38 Mitogen-Activated Protein Kinases; D021983:Cyclophilins; D002945:Cisplatin