A New Route to p38

Abstract

In a pair of back-to-back studies, Salvador et al. defined a new pathway to activation of the mitogen-activated protein kinase (MAPK) p38 in T cells and identified a suppressor of signaling through this pathway. MAPKs are activated in numerous cell types through a well-known cascade in which MAPK kinase kinases (MAPKKKs) activate MAPK kinases (MAPKKs), which activate MAPKs (see Rudd). Salvador et al. found that, in CD4 + T cells, T cell receptor (TCR) stimulation led to autophosphorylation of p38 MAPK through a process that did not require the conventional MAPK cascade. TCR-mediated phosphorylation of p38 did not depend on linker of activated T cells (LAT), although LAT was necessary for phosphorylation of the MAPKs ERK1/2 (extracellular signal-regulated kinase 1 and 2). The Src tyrosine kinase Lck was required for activation of p38, as was the tyrosine kinase Zap70. The TCR-mediated alternative pathway involved p38 phosphorylation on tyrosine 323 (Tyr 323 ), leading to autophosphorylation of p38, as well as to phosphorylation of its substrates. Although Lck and Zap70 both phosphorylated p38 on Tyr 323 in vitro, analysis of cells lacking Zap70 suggested that Zap70 acted downstream of Lck in p38 activation. Gadd45α (growth arrest and DNA damage-inducible gene) is an inhibitor of activation-induced T cell proliferation whose absence leads to hyperresponsive T cells and a lupus-like syndrome in mice. The same group showed that unstimulated T cells lacking Gadd45α exhibited enhanced p38 activity. Gadd45α directly inhibited p38 activity and also inhibited phosphorylation of p38 on Tyr 323 by Zap70. Constitutive Tyr 323 phosphorylation, autophosphorylation, and activation of p38 in Gadd45a −/− T cells were attenuated by inhibitors of Src tyrosine kinases. Thus, Gadd45α appears to prevent constitutive activation of T cell p38 through the alternative activation pathway. J. M. Salvador, P. R. Mittelstadt, T. Guszcynski, T. D. Copeland, H. Yamaguchi, E. Appella, A. J. Fornace Jr., J. D. Ashwell, Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat. Immunol. 6 , 390-395 (2005). [PubMed] J. M. Salvador, P. R. Mittelstadt, G. I. Belova, A. J. Fornace Jr., J. D. Ashwell, The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway. Nat. Immunol. 6 , 396-402 (2005). [PubMed] C. E. Rudd, MAPK p38: Alternative and nonstressful in T cells. Nat. Immunol. 6 , 368-370 (2005). [PubMed]