Figure 17.

Overview of signaling pathways affected by hSDC1 overexpression in DEN-induced hepatocarcinogenesis. EGF interacts with shed SDC1 through binding to HS to create a ternary complex with EGFR that triggers its activation. Decreased activity of receptor tyrosine kinases such as MET, PDGFR, insulin receptor, and AXL, and most likely of Wnt, may result from increased SDC1 shedding, as growth factors bound to the HS chains of SDC1 are removed from the vicinity of their receptors. Consequently, the activities of PIKC3, PDK1, and Akt are downregulated. Although the mechanism of Akt pSer473 downregulation by mTORC2 requires further investigation, downregulation of insulin receptors or PDGFR are likely candidates. Impaired activity of Akt is indicated by decreased inactivating phosphorylation of GSK3, Foxo1 and IkB. The mTOR pathway is further inhibited via feedback phosphorylation of mTOR by pS6K. Upregulation of CaMKII and decrease in Rac interferes with the noncanonical pathway of β-catenin. Besides their implication in cell metabolism, both Foxo1 and p53 upregulate the CDK inhibitors p21 and p27. Together with the downregulation of c-myc and cyclinD1, the overall outcome of these events is the inhibition of cell proliferation.