Fig. 1.

Canonical and non-canonical pathway effects of STAT3 on energy metabolism.

Canonical STAT3 signaling is activated by its tyrosine phosphorylation, which enables STAT3 to regulate transcription of its target genes. In addition to regulating genes controlling proliferation, survival and self-renewal, STAT3 both directly and indirectly regulates the expression of genes important for energy metabolism. Consequently, canonical STAT3 transcriptional activation favors glycolysis over oxidative phosphorylation as the cellular mechanism of ATP production. Non-canonical STAT3 function occurs via STAT3 phosphorylation at Ser727. Serine phosphorylated STAT3 can regulate the transcription of target genes. In addition, pS-STAT3 can be transported into the inner mitochondrial membrane where it enhances the activity of ETC complexes, stimulating OXPHOS and increased ATP production.

ATP, adenosine triphosphate; CDK1, cyclin-dependent kinase 1; ETC, electron transport chain; GLUT1, glucose transporter 1; GRIM-19, gene associated with retinoid-IFN-induced mortality; HIF1α, hypoxia inducible factor 1α; LDHA, lactate dehydrogenase; OXPHOS, oxidative phosphorylation; PKC δ, protein kinase C δ; STAT3, signal transducer and activator of transcription 3; TBK1, TANK-binding kinase 1.