Schematic model linking IL-3 regulation of metabolism with apoptosis and cytochrome c release. IL-3 signaling activates multiple pathways, but includes activation of JAK-type kinases, STAT transcription factors, Ras, Raf, MAP-K, and Akt.55-62 MAP-K activation and increase in cytoskeletal assembly/remodelling during growth creates an ATP demand and therefore an increase in glycolysis (left side, solid lines). Simultaneously, Raf targeted to the mitochondria by bcl-2, and/or Akt, phosphorylates BAD⁵⁵ that sequesters it to cytoplasmic 14-3-3 protein56 (right side, solid lines). Withdrawal of IL-3 leads to reduced Raf, Akt, and MAP-K activity, loss in cytoskeletal assembly, decline in ATP demand,19 and downregulated glycolysis. Coincidentally, unphosphorylated BAD is redirected to heterodimerise with mitochondrial bcl-2/bcl-X_L, which releases cytochrome c irrespective of ▵ψ_m, activates caspase III (CPP32), and CAD. Exogenous cytochrome c bypasses IL-3 signaling and directly activates caspase III. Although activation of MAP kinases in the MAP-KK A12 and A15 overexpression mutants has been difficult to demonstrate,24 overexpressed activated MAP-KK upregulates Bcl-X_L (M. Collins, personal communication, 1998). This would explain why A2 and A15 cells have increased survival on IL-3 withdrawal but are still induced by exogenous cytochrome c.