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Fig. 7. Model of insulin signaling through HIF/Sima. The activated InR can signal through AKT to prevent TSC1-TSC2 from inhibiting TOR, thereby activating S6K leading to growth stimulation. In addition, TOR can activate Sima/HIF-1 that induces transcription of several target genes, including scylla/RTP801 that in turn stimulates TSC1-TSC2, resulting in a negative feedback loop that reduces TOR activity. Activated AKT can stimulate nuclear localization of Sima/HIF-1 through an unknown mechanism (dashed line), contributing to the negative regulation of TOR. Low oxygen levels can inhibit growth by reducing the activity of Hph/Fatiga, which provokes stabilization of HIF-{alpha}/Sima and, in consequence, induction of scylla/RTP801, thereby reducing TOR activity.