In response to extracellular stimuli, the Raf/MEK/extracellular signal-regulated kinase (ERK) pathway regulates diverse cellular processes. While mainly known as a mitogenic signaling pathway, the Raf/MEK/ERK pathway can mediate not only cell proliferation and survival but also cell cycle arrest and death in different cell types. Growing evidence suggests that the cell fate toward these paradoxical physiological outputs may be determined not only at downstream effector levels but also at the pathway level, which involves the magnitude of pathway activity, spatial-temporal regulation, and non-canonical functions of the molecular switches in this pathway. This review discusses recent updates on the molecular mechanisms underlying the pathway-mediated growth inhibitory signaling, with a major focus on the regulation mediated at the pathway level.

Dysregulated Raf/MEK/extracellular signal-regulated kinase (ERK) signaling, a common hallmark of tumorigenesis, can trigger innate tumor-suppressive mechanisms, which must be inactivated for carcinogenesis to occur. This innate tumor-suppressive signaling may provide a potential therapeutic target. Here we report that mortalin (HSPA9/GRP75/PBP74) is a novel negative regulator of Raf/MEK/ERK and may provide a target for the reactivation of tumor-suppressive signaling of the pathway in cancer. We found that mortalin is present in the MEK1/MEK2 proteome and is upregulated in human melanoma biopsy specimens. In different MEK/ERK-activated cancer cell lines, mortalin depletion induced cell death and growth arrest, which was accompanied by increased p21^CIP1 transcription and MEK/ERK activity. Remarkably, MEK/ERK activity was necessary for mortalin depletion to induce p21^CIP1 expression in B-Raf^V600E-transformed cancer cells regardless of their p53 status. In contrast, in cell types exhibiting normal MEK/ERK status, mortalin overexpression suppressed B-Raf^V600E- or ΔRaf-1:ER-induced MEK/ERK activation, p21^CIP1 expression, and cell cycle arrest. Other HSP70 family chaperones could not effectively replace mortalin for p21^CIP1 regulation, suggesting a unique role for mortalin. These findings reveal a novel mechanism underlying p21^CIP1 regulation in MEK/ERK-activated cancer and identify mortalin as a molecular switch that mediates the tumor-suppressive versus oncogenic result of dysregulated Raf/MEK/ERK signaling. Our study also demonstrates that p21^CIP1 has dual effects under mortalin-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death.