sellekchem In other words, RSK2 activation acts as the convergent point for both RON Erk1/2 and TGF b receptor I/II Smad pathways leading to complete EMT. The importance of RSK2 in RON signaling also estab lishes a critical link to other Inhibitors,Modulators,Libraries signaling molecules observed in MSP induced EMT and cell migration. Acti vation of Erk1/2 is required for MSP induced EMT. As a downstream molecule of the Erk1/2 path way, RSK2 transduces MSP induced and Erk1/2 mediated signal for EMT as demonstrated in this study. In breast cancer cells, NF B activation is implicated in RON mediated cellular motility. RSK is known to activate NF B by phosphorylating NF B inhibitor I Ba and inducing its degradation. This finding suggests that the observed NF B activity in MSP sti mulated breast cancer cells could be channeled through RON activated RSK2.

In colon cancer cells stimulated by MSP, increased b catenin accumulation contributes to spindle like morphologies with increased migration. RSK2 activation is known to increase steady state of b catenin through Inhibitors,Modulators,Libraries phosphorylation and inhibition of a b catenin regulator GSK 3b. These activities imply that the Inhibitors,Modulators,Libraries RON mediated inhibition of Inhibitors,Modulators,Libraries GSK 3b could be caused by MSP induced RSK2 activation. The role of MSP activated AKT activity in cell migration is another example. Currently, evidence of direct RSK activation by AKT is not available. In contrast, studies have indicated that RSK is a mediator of growth factor induced activation of PI 3 kinase and AKT in epithelial cells. Thus, it is likely that MSP induced AKT acti vation is mediated by RSK.

Such activation facilitates AKT in regulating MSP induced cell migration. Consid ering Inhibitors,Modulators,Libraries all these facts, we reasoned that RSK is centered in MSP induced and RON mediated EMT with increased cell migration. Studies sing pancreatic L3. 6pl and colon HT 29 cells provide additional evidence showing the importance of RSK2 in MSP induced EMT like activity. First, we con firmed results derived from the MDCK cell model and demonstrated that RSK2 but not RSK1 is selectively involved in regulating RON mediated EMT and asso ciated cell migration. In the L3. 6pl cell model, only RSK2 specific siRNA prevented MSP induced EMT and cell migration. Second, we demonstrated that MSP induced EMT like phenotype is dependent on RSK2 expression and activation. In L3.

6pl cells that express regular levels of RSK1 and RSK2, MSP induces EMT like phenotypes featured by elongated cell morphology, reduced E cadherin expression, and increased vimentin expression. In contrast, these activities were not observed in HT 29 cells that express minimal levels of AZD9291 mechanism RSK1 and RSK2. HT 29 cells express both RON and oncogenic variant RON160 and both regulate HT 29 cell growth. However, MSP fails to induce EMT and migration in HT 29 cells, which provides indirect evidence indicating the role of RSK2 in MSP induced EMT and cell migration.