Figure 7. Proposed mechanism of US28 induced activation of the HIF-1α/PKM2 feedforward loop.

US28 constitutively stimulates Gα_q-dependent signaling cascades resulting in CaMKII activity and subsequent stimulation of the Akt/mTOR cascade to increase HIF-1α translation and/or stability. HIF-1α translocates to the nucleus and dimerizes with HIF-1β to form a functional HIF-1 transcription factor that binds HRE regions to regulate HIF-1 target genes supporting proliferation, angiogenesis and metabolic reprogramming. US28 signaling modulates PKM2 phosphorylation and rearrangement into enzymatically less active, but transcriptional active dimers. Dimeric PKM2 is linked with glycolysis and thus increased levels lactate production and secretion. PKM2 dimers and HIF-1α engage in a feedforward loop supporting a proliferative, angiogenic and glycolytic phenotype.