Fig. 3

Regulation of SREBP1 and lipid metabolism by oncogenic signaling in CSCs. Oncogenic PI3K (H1047R)- and K-Ras (G12 V) activates SREBP1 and SREBP2 to support de novo lipid synthesis and cell growth. The mTOR signaling regulates SREBP1 level through both transcriptional or translational mechanisms. Activation of PI3K.AKT/mTOR signaling pathway or FGFR3 leads to stabilization of SREBP1 protein and promotes SREBP1 translocation to nucleus. Mitotic kinase Cdk1 and Plk1 physically interact with nuclear SREBP1 protein. Sequentially phosphorylation of SREBP1 by Cdk1 and Plk1 blocks binding between the ubiquitin ligase Fbw7 and SREBP1 and attenuates SREBP1 degradation. Upon EGFR signaling activation, the nuclear form of PKM2 physically interacts with SREBP1, activating SREBP target gene expression and lipid biosynthesis