The p38 pathway provides negative feedback for Ras proliferative signaling

Ras activates three mitogen-activated protein kinases (MAPKs) including ERK, JNK and p38. Whereas the essential roles of ERK and JNK in Ras signaling has been established, the contribution of p38 remains unclear. Here we demonstrate that the p38 pathway functions as a negative regulator of Pas proliferative signaling via a feedback mechanism. Oncogenic Ras activated p38 and two p38-activated protein kinases, MAPK-activated protein kinase 2 (MK2) and p58-related/activated protein kinase (PRAK). MK2 and PRAK in turn suppressed Pas-induced gene expression and cell proliferation, whereas two mutant PRAKs, unresponsive to has, had little effect. Moreover, the constitutive p38 activator MKK6 also suppressed Pas activity in a p38-dependent manner whereas arsenite, a potent chemical inducer of p38, inhibited proliferation only in a tumor cell line that required Pas activity. MEK was required for Ras stimulation of the p38 pathway. The p38 pathway inhibited Pas activity by blocking activation of JNK, without effect upon ERK, as evidenced by the fact that PRAK-mediated suppression of Pas-induced cell proliferation was reversed by coexpression of JNKK2 or JNK1. These studies thus establish a negative feedback mechanism by which Pas proliferative activity is regulated via signaling integrations of MAPK pathways.