MAPK1 and neoplasm: Interestingly, each S1 and S2 domain mediates specific downstream effects, S1 directs Src and the PI3K-mediated trafficking of intact TRα from the cytoplasm to the nucleus and causes the transcription of HIF1A. In contrast, S2 activates MAPK1 and MAPK2, which then promotes the nuclear uptake of TRβ1 from the cytoplasm and leads to the proliferation of tumour cells [19,39,40].