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- Worms in space |
Recent work with Caenorhabditis elegans in the Jacobson lab has shown that in normal muscle, protein degradation is controlled by the balance between two hormone-regulated signaling pathways. Much of this was the work of Nate Szewczyk (left), a former graduate student who is now at NASA. Signaling by two forms of Fibroblast Growth Factor: Protein degradation in muscle is promoted by signal from two forms of FGF, acting redundantly on a single FGF receptor (EGL-15). The receptor can be activated by a mutation in a receptor tyrosine phosphatase. Genetic evidence shows that signal is transduced downstream by the Ras-Raf-MEK-MAPK cascade (see Figure below) and biochemical evidence shows that activation of FGFR provokes phosphorylation (activation) of MAPK. Previous work (Szewczyk, Peterson & Jacobson, 2002) had shown that mutational activation of Ras or of MAPK is sufficient to induce protein degradation. Protein degradation was prevented when both FGF-like ligands (EGL-17 and LET-756) were mutated, but not by either single mutation, implying that the two FGFs act redundantly to activate FGFR in muscle. Thus, either is sufficient and at least one is necessary to activate FGFR (see Szewczyk & Jacobson 2003). Low insulin signaling: Mutational or drug inhibition of signaling in the IGFR-PI3K-PDK-Akt pathway promotes muscle protein degradation. Temperature upshift of daf-2ts (IGFR) or age-1ts (PI3K) mutants or drug inhibition of PI3K provokes protein degradation (see figure, below). Brant Peterson (left), a former undergraduate who is now at Berkeley, showed that this is the result of intramuscular signaling, since degradation is prevented by muscle-specific expression of transgenes daf-2+ or age-1+. Conversely, mutational activation downstream opposes protein degradation. This effect of low IGFR signal occurs by releasing inhibition of the Ras pathway, insofar as reduction-of-function mutations in Raf, MEK or MAPK prevent the protein degradation induced by an inhibitor of PI3K or by a temperature-sensitive PI3K mutation. [Szewczyk, Peterson, Parkinson & Jacobson, in preparation].
One surprising implication of these studies is that Ras oncogene signaling is normally "on" in muscle, but its effect is suppressed at the level of Raf by signal from the IGFR pathway, which is also normally "on". Thus, in normal muscle two signaling pathways balance each other to prevent muscle protein degradation. This balance must be precariously poised, since lower IGFR signal or increased FGFR signal can each tip the balance in favor of protein degradation. These findings suggest a new view of how signaling occurs to provoke protein degradation: Rather than proteolysis being triggered when a single signal is turned from "off" to "on", what is important is the balance between two or more sets of signals with opposing effects. We believe this makes sense from a physiological viewpoint, in that muscle must monitor a variety of physiological variables and enter the state of protein catabolism when "unfavorable" signals are too high or "favorable" signals are too low. |
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