MAPKs (mitogen-activated protein kinases), including ERK (extracellular signal-regulated kinase), JNK (c- Jun NH2-terminal kinase), and p38, are known to play a critical role in transduction and regulation of Ras oncogene activity by phosphorylation-dependent mechanisms. Our previous work demonstrated that Ras activates the p38 pathway, which in turn inhibits Ras proliferative activity by negative feedback. Here we propose that Ras activates p38gamma MARK by increasing its expression without stimulating its phosphorylation, and induced p38gamma is required for Ras transformation through a physical interaction with ERK proteins independent of phosphorylation. This activity of p38gamma contrasts with that of its family member p38alpha, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. This hypothesis is based on our preliminary studies showing that K-Ras induces p38gamma protein expression but inhibits its phosphorylation, and that depletion of induced p38gamma suppresses K-Ras transformation in rat intestinal epithelial IEC-6 cells. Furthermore, gene arrays showed that p38gamma transcripts are increased in a set of primary human colon cancers than in matched normal tissues. The following specific aims will test this hypothesis: I) To demonstrate that p38gamma acts downstream of the MEK/ERK pathway to promote Ras transformation independent of phosphorylation;II) To determine whether p38gamma is required for Ras transformation through a complex formation with ERK proteins;III) To investigate if p38gamma is up-regulated in K-Ras mutated human colon cancer and required for K-Ras-dependent malignant growth in vitro and in mice. This study will demonstrate a novel function of stress p38gamma MARK as a Ras effector through induced expression independent of phosphorylation and thereby reveal a mechanism by which Ras oncogene activity is determined by a signaling integration between anti-oncogenic p38alpha and pro-oncogenic p38gamma. Information obtained will directly contribute to human colon cancer prevention and treatment by demonstrating the diagnostic value of increased p38gamma expression and the therapeutic significance of p38gamma depletion.
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