Fig. 3

Schematic representation of IGF signaling regulation in EMT. Ligand activation of IGF-IR results in intrinsic tyrosine kinase phosphorylation and activates two main signaling pathways, ①IRS-1/PI3K/Akt and ②Ras/Raf/ERK pathways. Both of these two main pathways regulate transcription factors of ZEB, Snail and Twist families those are all involved in the EMT program. In addition, Slug increases IGF-I transcription which potentiates the progression of EMT. On the other hand, crosstalk between other signaling pathways and IGF signaling are also involved in EMT program. ③IGF-I stimulates β-catenin relocation and stability through the inactivation of GSK-3β which initiates Wnt signaling. Furthermore, IGF-I cooperates with Wnt signaling pathway in the metastasis process by stimulating TCF/LEF-dependent transcription through the Akt/GSK-3β/β-catenin pathway. ④GSK-3β binds to and phosphorylates Snail at two consensus motifs to regulate the biological functions of Snail. ⑤Notch-1 directly up-regulates IGF-IR protein and mRNA expression and amplifies the mitogenic effects of IGF-IR/PI3K signaling that potentiates EMT program.⑥Shh signaling activation mediates EMT process through up-regulation of IRS-1 and Snail