title: T cell receptor-mediated activation of p38{alpha} by mono-phosphorylation of the activation loop results in altered substrate specificity.
abstract: p38 MAPKs are typically activated by upstream MAPK kinases that phosphorylate a Thr-X-Tyr motif in the activation loop. An exception is the T cell antigen receptor signaling pathway, which bypasses the MAPK cascade and activates p38alpha and p38beta by phosphorylation of Tyr-323 and subsequent autophosphorylation of the activation loop. Here we show that, unlike the classic MAPK cascade, the alternative pathway results primarily in mono-phosphorylation of the activation loop residue Thr-180. Recombinant mono-phosphorylated and dual phosphorylated p38alpha differed widely with regard to activity and substrate preference. Altered substrate specificity was reproduced in T cells in which p38 was activated by the alternative or classical MAPK pathways. These findings suggest that T cells have evolved a mechanism to utilize p38 in a specialized manner independent of and distinct from the classical p38 MAPK signaling cascade.
authors.affiliation: Laboratory of Immune Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mittelstadt
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell