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PATHOLOGY
Death and Survival Proteins: An Unexpected PartnershipThe fine line between life and death is even flimsier in the cellular realm than in the human. At any given moment, a cell might be commanded to commit suicide. As if to reinforce the ever-present possibility of death, the cell stations many of its death proteins at those hubs of metabolic activity, the mitochondria. Yet, even in this precarious world, life-sustaining activities such as glucose metabolism were thought to be carried out by entirely different proteins from those involved in apoptosis.
Cell death proteins BAK and BAD partner with life-sustaining molecules. At right, the cell begins its descent into death when BAD, one of a trio of BH3-only death proteins, sends a signal to BAK. Normally restrained by VDAC2, BAK is released from the ion channel's grip. Once activated, BAK punches a pore in the mitochondrion, releasing cytochrome c and triggering a cascade of cell-destroying enzymes (apoptosome). In liver cells, BAD was found to reside at the mitochondria in a complex with PKA, PP1, WAVE-1 (a scaffold for PKA), and surprisingly, glucokinase (left). (Images adapted from originals by Eric Smith) "People in the field always thought glucose metabolism and apoptosis were two independent pathways for the cell," said Nika Danial, HMS research fellow in pathology at the Dana-Farber Cancer Institute. But the line between survival and extinction may be growing more tenuous. Danial, Emily Cheng, Stanley Korsmeyer, and colleagues have discovered that two of the cell's most notorious death proteins, BAK and BAD, have intimate partnerships with life-sustaining molecules and may help them carry out their survival activities. The findings, reported in two separate papers, could hold clues to new approaches for treating diseases as disparate as hepatitis, diabetes, and certain cancers. In some cases, the goal would be to prolong the lives of cells; in another--that of cancer--to get them to die more quickly. The Cell's ExecutionersProteins do not get much deadlier than the duo BAK and BAD. BAK works by punching holes in the mitochondria, releasing the toxin cytochrome c into the cytosol, which triggers a cascade of cell-destroying enzymes, the caspases. Cheng, HMS instructor in pathology at DFCI, and colleagues discovered that BAK, when not performing its executioner's role, is kept in check by VDAC2, a member of an ion channel family. Their findings appear in the July 31 Science.
Work on the interaction between death signals and survival proteins was carried out by (from left) Stanley Korsmeyer, Emily Cheng, and Nika Danial. (Photos by Graham Ramsay) BAD's main role is to prevent other proteins, in particular BCL2, from interfering with BAK at the mitochondria. Analyzing liver cells, Danial and colleagues found that BAD resides in this location in a complex with four other proteins, including the metabolic protein glucokinase. These findings appear in the Aug. 21 Nature. "The big surprise was finding glucokinase," said Danial. While two other proteins in the complex are known to phosphorylate or dephosphorylate BAD, that is not true of glucokinase, which phosphorylates glucose. What exactly glucokinase and BAD are doing together is not clear, but it seems that at least one member of the pair needs the other. When BAD was knocked out in cultured liver cells and in mice, glucokinase's ability to phosphorylate glucose was blunted. In fact, BAD knockout mice exhibited fasting hyperglycemia and other symptoms associated with diabetes.
"BH3s like BAD are kind of like the sentinels looking around for minimal damage in the cell, for death and survival signals, trying to instruct the cell to do the right thing, either live or honorably die through apoptosis," said Korsmeyer, the Sidney Farber professor of pathology. "The issue is, can you be a guardian recognizing damage without being intimately embedded in the pathway?" The answer suggested by Danial, and also by the work of Cheng, is no. Getting Your BAK UpIt was a concern with the bigger picture that motivated both researchers in the first place. Building on previous work in Korsmeyer's lab, Cheng knew that BAK is activated by a set of signaling proteins. But it was not clear how these proteins were rousing BAK. Thinking that they might work by releasing BAK from the grip of some unknown restraining protein, Cheng embarked on a series of crosslinking experiments to see which proteins might have a strong affinity for BAK. When the one solid candidate turned out, upon purification, to be the ion channel VDAC2, Cheng was surprised. "I was looking for a novel gene," she said, or at the very least, an anti-apoptotic protein like BCL2.Whether the relationship goes the other way--that is, whether BAK is required for VDAC2 to carry out its function as an ion channel--is not clear. "That is the next step for us," said Cheng. The possibility for reciprocity is also one that Danial intends to explore. It is clear from her knockout results that BAD must be present for glucokinase to phosphorylate glucose. But there are hints that BAD may benefit from the relationship with the glucose-metabolizing machinery, possibly by sensing whether the cells have enough of this critical resource to survive. Normally, cells undergo apoptosis when deprived of glucose. Danial found that liver cells lacking BAD did not commit suicide. "We had the feeling that BAD is sensing glucose to tell glycolysis to occur, but also to talk to the apoptotic machinery downstream," she said. "So it is cross-talking between the two pathways." Speculating on the origins of this link, Korsmeyer suggests that BAD and other death proteins might even have started out as part of the glucose-metabolism pathway. "Mitochondria were separate organisms and were internalized during evolution. Ancient eukaryotes were probably sugar-dependent and later evolved proteins that regulated cell survival," he said. "We might wonder whether BAD's primordial role did not have more to do with sugar in controlling survival, and that as organisms grew up and got more cell types, they evolved this pathway specifically for integrating death and survival signals." --Misia Landau |
