MAPKK-independent activation of p38[alpha] mediated by TAB1-dependent autophosphorytation of p38[alpha]

Phosphorylation of mitogen-activated protein kinases (MAPKs) on specific tyrosine and threonine sites by MAP kinase kinases (MAPKKs) is thought to be the sole activation mechanism. Here, we report an unexpected activation mechanism for p38[alpha] MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38[alpha] with TAB1 [transforming growth factor-[beta]-activated protein kinase 1 (TAK1)--binding protein 1] leading to autophosphorylation and activation of p38[alpha]. We detected formation of a TRAF6-TAB1-p38[alpha] complex and showed stimulus-specific TAB1-dependent and TAB1-independent p38[alpha] activation. These findings suggest that alternative activation pathways contribute to the biological responses of p38[alpha] to various stimuli.