Molecular Pathways: BRAF Induces Bioenergetic Adaptation by Attenuating Oxidative Phosphorylation

Growth factor mediated activation (EGF) of a receptor tyrosine kinase (EGFR) leads to downstream pathway signaling along the RAS-RAF-MEK-MAPK and PI3K-AKT-mTOR pathways. Key convergence points are MAPK mediated suppression of LKB1/AMPK energy sensing, and AKT activated translocation of the glucose transporter GLUT4 to the plasma membrane leading to augmented glucose import for anabolic (nucleotides, lipids, and amino acids) in addition to catabolism towards ATP regeneration in the mitochondria utilizing the proton gradient. Furthermore, MAPK stabilizes and mTOR increases translation of HIF1α, triggering the transcriptional function with effects on reducing pyruvate decarboxylation/oxidation to acetyl-CoA (Ac-CoA) destined for use in the TCA cycle. In melanoma cells, HIF1α activity reduces expression of MITF-PGC1α levels and thereby causes effects on reducing mitochondrial bioactivity (OXPHOS, ROS protection) in addition to differentiation associated cascades. Frequently mutant components (and pathways) in human cancers are indicted in red. Inhibitors of indicated pathway components are indicated in blue.

Publication

Molecular Pathways: BRAF Induces Bioenergetic Adaptation by Attenuating Oxidative Phosphorylation. () Rizwan Haq, et al. Clin Cancer Res. ;20(9):2257-2263. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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