Regulation of HIF-1α by the MAPK pathway. Stimulation of receptor tyrosine kinases (RTKs) by growth factors, or activating mutations in the RAS family of GTPases, such as KRAS, results in activation of a range of MAPK-signalling proteins. Activation of ERK1/2 by MEK1/2 increases HIF-1 signalling (a) by phosphorylating and promoting the interaction of the coactivator p300 with HIF-1α and (b) by phosphorylating and activating the translational regulatory protein p70S6K and by phosphorylating and disrupting the repressive interaction of 4E-BP1 with eIF-4E. Activation of these translational machinery proteins leads to increased protein synthesis of HIF-1α. Activation of MAPKs (p38/p38γ) leads to the direct phosphorylation and activation of HIF-1α. Additionally, under hypoxia, activation of the small GTPase Rac1 leads to a Rac1 dependent increase in HIF-1α activity via Rac-1 induced activation of p38 MAPK. Genetic mutations in members of the MAPK signalling pathway such as those in BRAF (BRAFV600E) lead to hyperactive MEK/ERK signalling and enhanced HIF-1α activity.
