The p38 MAPK stress pathway as a tumor suppressor or more?

Abstract

p38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases that together with ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) MAPKs act to convert different extracellular signals into specific cellular responses through interacting with and phosphorylating downstream targets. In contrast to the mitogenic ERK pathway, mammalian p38 MAPK family proteins (alpha, beta, gamma, and delta), with and without JNK participation, predominantly regulate inflammatory and stress response. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and -independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. A selective activation of a stress pathway to block tumorigenesis may be a novel strategy to control human malignancies.

Figure 1

An opposing role of the ERK and p38 pathways in Ras transformation. The ERK activity is required for Ras transformation and the ERK activation alone is sufficient to transform cells. The p38 MAPK pathway, as demonstrated with p38alpha, on the other hand, is inhibitory to Ras oncogene signaling. Thus, the ERK and p38 MAPK pathways oppose each other in determining Ras transforming activity. The inconsistent effect of the JNK pathway on Ras transformation was illustrated with the “+” sign, whereas “?” indicates that p38beta, gamma and delta proteins may have a distinct role in regulating Ras oncogene activity.

Figure 2

p38 pathways regulate Ras oncogene activity by negative feedback (A) and signaling integration (B). Along the p38 pathway, MKK6, p38alpha and MK2/PRAK have been shown to be activated by Ras oncogene through MEK/ERK pathways and in turn suppress Ras activity by negative feedback (A) (60). The p38gamma expression, on the other hand, is induced by Ras that is required for Ras transformation (72). Phosphorylated p38alpha was recently shown to down-regulate p38gamma protein expression by ubiquitin/proteasome pathways (74). In a given system, therefore, the Ras transforming activity will be determined by integrated signaling from the Ras-suppressor p38alpha and the Ras-effector p38gamma (B) (72, 74). Solid lines were used for elucidative purpose and detail pathways for these regulations remain to be established.