Src activates HIF-1α not through direct phosphorylation of HIF-1α-specific prolyl-4 hydroxylase 2 but through activation of the NADPH oxidase/Rac pathway

Src activates HIF-1α not through direct phosphorylation of HIF-1α-specific prolyl-4 hydroxylase 2 but through activation of the NADPH oxidase/Rac pathway

Ho-Youl Lee, Taekyong Lee, Naery Lee, Eun Gyeong Yang, Cheolju Lee, Jonghyun Lee, Eun-Yi Moon, Joohun Ha and Hyunsung Park

Carcinogenesis (2011) doi: 10.1093/carcin/bgr034 First published online: February 18, 2011


Hypoxia-Inducible Factor (HIF)-1α/β heterodimer is a master transcription factor for several genes involved in angiogenesis, glycolysis, pH balance, and metastasis. These HIF-1 target genes help tumors to overcome forthcoming metabolic obstacles as they grow. Under normoxic condition, the HIF-1α subunit is hydroxylated by its specific prolyl-4 hydroxylase 2, given the acronym PHD2. Hydroxylated HIF-1α becomes a target for von Hippel-Lindau (VHL) which functions as an E3 ubiquitin ligase. Src prevents hydroxylation-dependent ubiquitinylation of HIF-1α, thus stabilizing it under normoxic conditions. We found that active Src does not directly phosphorylate any tyrosine residue of PHD2. In vitro hydroxylation reaction showed that the presence of the purified active Src protein does not inhibit the hydroxylation activity of the purified PHD2 enzymes. Instead of directly inhibiting PHD2, Src recruits several down-stream signaling pathways to intercept hydroxylation-dependent ubiquitinylation of HIF-1α. Using biochemical and genetic inhibition, we demonstrated that Src requires NADPH oxidase/Rac complex for stabilization of HIF-1α. We found that excess vitamin C treatment attenuates Src-induced HIF-1α activation. HIF-1α-hydroxylation dependent VHL pull down assay showed that Src inhibits cellular PHD2 activity by inducing ROS production in a mechanism involving Rac1-dependent NADPH oxidase. Src-induced ROS reduces cellular vitamin C which is required for the activity of PHD2, thus Src can block VHL recruitment of HIF-1α, leading to stabilization of HIF-1α

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