 cell-surface receptor. TORC2 appears to control endocytosis via Rho1, Ypk1, and possibly the Slm proteins, but how Rho1, Ypk1, and the Slm proteins are functionally related in mediating TORC2-controlled endocytosis is unknown (deHart et al. 2002, 2003; Bultynck et al. 2006).
A third TORC2-regulated process is sphingolipid biosynthesis (Powers et al. 2010). Sphingolipids serve as essential structural components in lipid bilayers and as signaling molecules. The first indication that TORC2 controls sphingolipid synthesis was the finding that overexpression of SUR1 suppresses a temperature-sensitive tor2 mutation (Helliwell et al. 1998a). In a parallel study, Beeler et al. (1998) reported that a mutation in TOR2 or AVO3 (also known as TSC11), or mutations in genes encoding components of the sphingolipid biosynthetic pathway, suppress a csg2 mutation. Sur1/Csg1 and Csg2 are subunits, probably the catalytic and regulatory subunits, respectively, of mannosylinositol phosphorylceramide synthase that mediates a late step in sphingolipid biosynthesis. The Slm proteins were subsequently also linked to sphingolipid metabolism (Tabuchi et al. 2006; Daquinag et al. 2007). Most recently, Aronova et al. (2008) profiled sphingolipids in a conditional avo3 mutant and thereby confirmed that TORC2 plays a positive role in sphingolipid biosynthesis. Aronova et al. (2008) also investigated the molecular mechanism by which TORC2 controls sphingolipids. They found that TORC2 regulates sphingolipid production via Ypk2 and suggest a model wherein TORC2 signaling is coupled to sphingoid long-chain bases (early intermediates in sphingolipid synthesis) to control Ypk2 and late steps in sphingolipid synthesis. Furthermore, the biosynthetic step controlled by TORC2 and Ypk2 is antagonized by the phosphatase calcineurin that is functionally linked to the Slm proteins (Bultynck et al. 2006; Mulet et al. 2006; Aronova et al. 2008). Another potential target for the regulation of sphingolipid biosynthesis by TOR are the Orm1 and Orm2 proteins. The conserved Orm proteins, identified as a potential risk factor for childhood asthma, form a complex that negatively regulates the first and rate-limiting step in sphingolipid biosynthesis (Breslow et al. 2010; Han et al. 2010). Both Orm1 and Orm2 are phosphoproteins and at least Orm1 phosphorylation changes upon rapamycin treatment (Huber et al. 2009; Soulard et al. 2010). Furthermore, loss of Orm2 suppresses a Ypk deficiency (Roelants et al. 2002; Schmelzle et al. 2002; Kamada et al. 2005; Mulet et al. 2006). These findings suggest that both TORC1 and TORC2 may control sphingolipid synthesis via Orm proteins.
Future Directions
What is upstream of the two complexes?
How TORC activities are altered in response to environmental cues remains a major void in our understanding of the TOR-signaling network. The TOR complexes are regulated by nutrients, stress, or ribosomes, but the mechanisms by which these inputs are sensed and how this information is transduced, with the notable exceptions discussed above, to ultimately regulate kinase activity remain largely unknown. Genetic screens, such as the reverse suppressor screen described above, should help to further elucidate these signaling pathways. Unlike growth factor-signaling pathways, which are present only in metazoans, nutrient and stress-responsive pathways are found in all eukaryotic cells, and thus their characterization in model organisms would have far-reaching implications.
What is downstream of the TORCs?
The TORCs play a central role in the regulation of cell growth by signaling to a staggering number of distal downstream processes. Recent phosphoproteomics studies have begun to illuminate the relevant phosphorylation cascades and, in addition, have suggested the existence of novel growth-related effectors downstream of TORC1. Similar studies describing the TORC2-dependent phosphoproteome are eagerly anticipated. Elucidating these downstream signaling events is both academically interesting and medically important; cell growth, like cell birth (division) and cell death, is a fundamental aspect of life, and pathological or pharmaceutical dysregulation of TOR pathways is clinically relevant. For example, unbridled ribosome biogenesis has been strongly implicated in cancer, and the motivation to understand the TORC1 effectors that modulate longevity is obvious. Thus, characterization of TOR pathways in yeast and mammals will identify potentially druggable factors whose targeting could yield therapeutic gain in any of several pathologies.
Acknowledgments
We thank Claudio De Virgilio and Michael Stahl for comments on the manuscript. We acknowledge support from the Cantons of Basel and Geneva, SystemsX.ch, the Frontiers in Genetics and Chemical Biology National Centers for Competence in Research, the European Research Council, the Louis-Jeantet and Leenaards Foundations, and the Swiss National Science Foundation.
Footnotes
Communicating editor: J. Thorner
- Received July 29, 2011.
- Accepted September 12, 2011.
Available freely online through the author-supported open access option.Our society, in many ways, is a violent society. Headlines in the newspaper, breaking news on television, reports on talk radio, all testify to how many people can be prone to use destructive and deadly force against others. Scripture recognizes the God-given authority of government to, in accordance with God's will, punish evildoers. "For he is a minister of God to thee for good. But if thou do that which is evil, be afraid; for he beareth not the sword in vain: for he is a minister of God, an avenger for wrath to him that doeth evil" (Romans 13:4).
What about the case for self-defense? What about those situations where an individual=s life is being threatened, where a person could face death if he or she doesn't respond? What does Scripture say can be done by those who could face the imminent reality of their own demise if they do not respond? There are those who would point us to Jesus' words in the Sermon on the Mount; "but I say unto you, resist not him that is evil: but whosoever smiteth thee on thy right cheek, turn to him the other also" (Matthew 5:39). In context, Jesus was addressing a backhanded blow to one's face, as the Greek term for smite, or strike, indicates an opened handed slap, in contrast to a blow with a clenched fist. Jesus was not addressing a life threatening event in this passage, but an insult.
There are other passages to consider. God established a basic principle when he told Noah, "And surely your blood, the blood of your lives, will I require; At the hand of every beast will I require it. And at the hand of man, even at the hand of every man's brother, will I require the life of man. Whoso sheddeth man's blood, by man shall his blood be shed: For in the image of God made he man" (Genesis 9:5-6). In the Law of Moses, God said, "If the thief be found breaking in, and be smitten so that he dieth, there shall be no bloodguiltiness for him" (Exodus 22:2). To His disciples, Jesus said, "But now, he that hath a purse, let him take it, and likewise a wallet; and he that hath none, let him sell his cloak, and buy a sword" (Luke 22:36).
In considering the possibility of defending one's life, or that of another, from harm or destruction, it must be emphasized, Scripture is speaking of acting in defense, not taking vengeance or acting as a vigilante, not initiating hostile actions against others. We pray no one would find themselves in such a situation in life, but the truth is, some have and some will. To respond in defending oneself has Biblical precedence. Every Christian's ultimate goal, however, is to reach others with the saving gospel of Jesus Christ, which transforms lives and offers the peace of God. "And be not fashioned according to this world: but be ye transformed by the renewing of your mind, and ye may prove what is the good and acceptable and perfect will of God" (Romans 12:2).Come and work in a unique care setting where you can really make a difference in the lives of other people.
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Heather House is a residential home providing Nursing care to a group of 16 younger adults who have visual impairments with complex physical, learning and healthcare needs. Most people living with us will receive palliative and end of life care.
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