Figure 9
Schematic model illustrating the effect of SHIP2 inhibition in CD2AP-deficient podocytes. (A) Wild type podocytes in basal state. CD2AP associates with SHIP2. CD2AP inhibits the production of ROS, and SHIP2 negatively regulates the pathways leading to AKT and ERK phosphorylation. The balance between the prosurvival and proapoptotic signals is maintained. (B) CD2AP−/− podocytes in basal state. The expression and activity of SHIP2 and generation of ROS are increased in the absence of CD2AP. Increased SHIP2 activity leads to low phosphorylation level of AKT and ERK. The expression of PDK1 is downregulated contributing to degreased phosphorylation of T308 of AKT. Decrease in prosurvival signalling manifests as increased apoptosis of the cells. (C) Inhibition of SHIP2 activity with AS1949490 in CD2AP−/− podocytes. Inhibition of the activity of SHIP2 leads to reduced generation of ROS. AS1949490 attenuates the potential of SHIP2 to negatively regulate AKT and ERK activity, yet the phosphorylation of S473 of AKT does not increase. Despite of low expression level of PDK1, the phosphorylation of T308 of AKT increases. As phosphorylation of both sites of AKT is required for its full activity, remains the balance between prosurvival and proapoptotic signalling disrupted and podocytes undergo apoptosis. It is also possible that increased ERK activation may contribute to an increase in apoptosis (see Discussion for details).
