Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals.

Introduction To maximize advantages and reduce costs associated with life as an interdependent community of cells, multicellular organisms have evolved common mechanisms to regulate the life and death of their individual cells. Critical to the health and survival of a multicellular organism is its ability to selectively sustain advantageous cells and selectively eliminate cells that threaten the survival of its cellular community. Therefore, regulated survival of individual cells evolved in a manner consistent with organismal and population survival priorities. The molecular signaling mechanisms that drive these life and death decisions have been the subject of intense research. This is because of their primary role in tissue development and maintenance and in the number of pathological states that may develop when such signaling goes awry. Excessive cell survival can lead to disorders such as cancer and autoimmunity, and insufficient cell survival can lead to tissue degenerative and developmental disorders. Efficient removal of cells that are damaged, malignant, or otherwise organismally threatening occurs by selectively triggering latent “self-destruction” machinery present in each cell. This regulated cell death can be triggered rapidly (death within 2–8 h) by activation of extracellular cell death receptors (see Refs. 1–3 for reviews on death receptor-mediated cell death). The union of a death ligand with its receptor initiates the assembly of a signaling complex around the cytoplasmic tail of the receptor. This complex recruits and activates cysteine proteases (caspases), the proteolytic activity of which leads to the demise of the cell (see Refs. 4 and 5) for reviews on caspases). Alternatively, cell death can be triggered by a relatively slow mechanism (roughly 8 h to 2 days) by removing the survival signals that normally sustain cells, keeping the cell death machinery at bay. This slower form of death appears to be primarily dependent on the regulation of mitochondrial integrity and/or function through modulation of Bcl-2 family members (see Refs. 6–10 for reviews on the Bcl-2 family). Loss of mitochondrial integrity leads to the release of agents such as cytochrome c and apoptosis-inducing factor that can lead to caspase-dependent or caspase-independent cell death, respectively (see Refs. 11–16 for reviews on mitochondria and cell death). Multicellular organisms produce a host of secreted and cell-tethered survival factors that cooperate with metabolic precursors to sustain the life of responsive tissues. Many cell types survive less than 12 h without constant support provided by survival factors. The molecular mechanisms whereby survival factors exert their effects are only beginning to be unraveled. The best understood and perhaps primary role of cell survival factors is to mobilize signaling molecules that ultimately protect the integrity of mitochondria (the focus of this review). However, in some cell types, these signaling cascades may also antagonize death induced by activated death receptors (17–21). The most dynamic players in cell survival signaling cascades are now being revealed and characterized. However, the regulatory complexity found in each cascade is not trivial. Multiple cascades can be simultaneously activated by one survival factor and a combination of survival factors can provide synergistic support. Additionally, differences in the expression levels of the receptors for specific survival factors can significantly alter the signal strength and final outcome of a given survival factor. It is thus challenging to evaluate the effect of the activity of one signaling pathway in isolation. Nevertheless, the molecular events propagated by distinct signaling pathways are currently emerging, revealing their economical use and synergistic targeting of common effector substrates. Fig. 1 shows the convergence of three core signaling pathways on two common effector substrates, the proapoptotic Bcl-2 family member, BAD, and the transcription factor CREB. In addition to the survival pathways shown in Fig. 1, several others have been identified. This review, however, will focus on the molecular mechanisms of mammalian cell survival mediated by canonical MAPK signaling. MAPK-dependent cell survival mechanisms have also been described in Drosophila (22, 23), but because these pathways have yet to show conservation in mammals, they will not be discussed here.