Figure 4.

Mechanisms leading to impaired cell signaling and transcriptional events. Decline in ARSB leads to accumulation of chondroitin 4-sulfate and dermatan sulfate. Decline in ARSB may be due to congenital mutation, hypoxia, increased exposure to chloride or phosphate, estrogen, ethanol, carrageenan, or other exposures, as indicated in Table 2 and Section 4. The signaling pathways were explored with chondroitin 4-sulfate (C4S), since a C4S antibody which detected C4S chains was available. Two major pathways are affected by increased C4S, as shown. Galectin-3 binds less to more highly sulfated C4S and becomes available for other interactions, including increased binding with the insulin Receptor, leading to inhibition of insulin signaling [80,81,82] and increased binding with transcription factors, enabling increased DNA binding and transcriptional effects [27,32,33,34,35]. In contrast, SHP2 binds more with C4S when ARSB is silenced, leading to reduced phosphatase activity [14,28,33,36,37,38] and sustained phosphorylation of critical signaling molecules, including phospho-ERK1,2 [33,36,83], phospho-JNK [28], and phospho-p38 MAPK [14,38]. Due to the complexity of the phospho-proteome, the manifestations of sustained phosphorylations impact multiple signaling events. These include increased c-Myc activation of DNMTs and increased methylation of DKK3, which when active acts as an inhibitor of Wnt signaling [36,37,38].