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. 2009 Nov 16;30(2):470–480. doi: 10.1128/MCB.00666-09

FIG. 9.

FIG. 9.

Schematic model of SAPK-induced Foxo3a nuclear export in muscle cells. Foxo3a transcription factor is a direct substrate of the Akt protein kinase. In the absence of growth factors or nutrients, PI3K/Akt pathway activation decreases and Foxo3a localizes within the nucleus, where it stimulates Atrogin-1 expression, thereby inducing muscle atrophy. When cells are exposed to growth factors/nutrients, the PI3K/Akt cascade is activated and triggers the export of Foxo3a to the cytoplasm. When the PI3K/Akt pathway is inhibited, stimulation of SAPKs induces Foxo3a nuclear export via the CRM1 nuclear export protein and partly prevents muscle atrophy by decreasing Atrogin-1 promoter (Atrogin-1 prom) activity. Alternatively, activated IKK can directly phosphorylate Foxo3a and promote Akt-independent Foxo3a nuclear export. Data for dominant-negative forms of Akt (DN mutants), the constitutively active forms of MKK3 and MKK4 (CA MKK3 and CA MKK4), LY294002 (inhibitor of PI3K), SC-514 (inhibitor of IKK), SB203580 (inhibitor of p38), SP600125 (inhibitor of JNK), leptomycin B (inhibitor of CRM1 nuclear export protein), and Hanks balanced salt solution (HBSS) (nutrient deprivation condition) are shown.