title: Activating p38 MAPK: new tricks for an old kinase.
abstract: Mitogen-activated protein kinases (MAPKs) participate in signaling initiated by a wide variety of extracellular stimuli. MAPKs are most commonly activated by a series of phosphorylation events in which one kinase phosphorylates another, the "MAPK cascade". The cascade concludes with the dual phosphorylation of MAPKs on a conserved Thr-X-Tyr motif. In the case of the p38 MAPK, an exception to this paradigm has been found when signaling via the T cell antigen receptor (TCR). Rather than trigger the MAPK cascade, TCR-mediated stimulation activates proximal tyrosine kinases, which results in the phosphorylation of p38 on a noncanonical activating residue, Tyr-323. This phosphorylation activates p38 to phosphorylate third party substrates as well as its own Thr-Gyl-Tyr motif. Here we discuss the structural and functional implications of this alternative p38 activation pathway, which may provide a new target for tissue-specific pharmacologic inhibition.
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. mittelsp@mail.nih.gov
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mittelstadt
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Salvador
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013912:Threonine / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; D013912:Threonine; D014443:Tyrosine; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases