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Huntingtin inhibits caspase-mediated cleavage of Pak2
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
Huntington's disease (HD) is an autosomal-dominant, progressive, neurodegenerative disorder resulting from a mutant form of the huntingtin gene (Htt). Wild-type Htt have less than 27 cytosine-adenine-guanine (CAG) repeats on its 5' end. Thirty-six or more repeats results in mutant Htt (muHtt, red node), which increases the rate of neuronal decay in certain types of neurons, affecting regions of the brain with a higher proportion or dependency on them.
The exact mechanism of cellular toxicity caused by mutant Htt is not completely understood, although many proteins have been identified as Htt-interacting partners. One of these partners is the p21-activated kinase 2 (pak2, green node), a serine-threonine kinase that is activated by small GTPases such as Cdc42 (blue node). In February of this year Htt was shown to physically interact with Pak2 and thus prevent Pak2 cleavage. Interestingly, it was found that muHtt partially inhibits cleavage of Pak2, although its effect was weaker than that of its wild-type counterpart.
Pak2 is activated via cleavage by caspase proteases to release a constitutively active C-terminal fragment (Pak2p34), which has been observed after cells are exposed to death stimuli such as Fas ligand (violet node). By binding to Pak2 and thus preventing its activation via cleavage, both wild-type Htt and muHtt abolish a pathway that is crucial for caspase-associated cell death. As muHtt is itself toxic owing to its gain-of-function properties, simple inferences regarding its potential anti-apoptotic properties cannot always be made, especially if conditions that might activate pathways that potentiate muHtt toxicity are considered. If muHtt expression enhances the toxicity of a specific toxin, then this might be due to the gain-of-function toxicity of the mutant protein, which could be unrelated to, or might indeed dominate, its anti-apoptotic properties.
Interestingly, caspase cleavage sites in Htt are also found and it has been suggested that cleavage of Htt may be a crucial step in aggregate formation and neurotoxicity in HD. In addition, prevention of fragmentation of muHtt or wild-type Htt allows it to maintain its ability to inhibit Pak2 cleavage, thus decreasing the toxicity resulting from Pak2p34. In conclusion, the functional links between Htt and Pak2 might provide leads for further understanding of cell death and cell survival.
The exact mechanism of cellular toxicity caused by mutant Htt is not completely understood, although many proteins have been identified as Htt-interacting partners. One of these partners is the p21-activated kinase 2 (pak2, green node), a serine-threonine kinase that is activated by small GTPases such as Cdc42 (blue node). In February of this year Htt was shown to physically interact with Pak2 and thus prevent Pak2 cleavage. Interestingly, it was found that muHtt partially inhibits cleavage of Pak2, although its effect was weaker than that of its wild-type counterpart.
Pak2 is activated via cleavage by caspase proteases to release a constitutively active C-terminal fragment (Pak2p34), which has been observed after cells are exposed to death stimuli such as Fas ligand (violet node). By binding to Pak2 and thus preventing its activation via cleavage, both wild-type Htt and muHtt abolish a pathway that is crucial for caspase-associated cell death. As muHtt is itself toxic owing to its gain-of-function properties, simple inferences regarding its potential anti-apoptotic properties cannot always be made, especially if conditions that might activate pathways that potentiate muHtt toxicity are considered. If muHtt expression enhances the toxicity of a specific toxin, then this might be due to the gain-of-function toxicity of the mutant protein, which could be unrelated to, or might indeed dominate, its anti-apoptotic properties.
Interestingly, caspase cleavage sites in Htt are also found and it has been suggested that cleavage of Htt may be a crucial step in aggregate formation and neurotoxicity in HD. In addition, prevention of fragmentation of muHtt or wild-type Htt allows it to maintain its ability to inhibit Pak2 cleavage, thus decreasing the toxicity resulting from Pak2p34. In conclusion, the functional links between Htt and Pak2 might provide leads for further understanding of cell death and cell survival.
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