uPAR and cathepsin B-mediated compartmentalization of JNK regulates the migration of glioma-initiating cells.
Bottom Line: We also observed that knockdown of uPAR and cathepsin B regulated the Ras-Pak-1 pathway to induce the translocation of p-JNK from cytosol to nucleus.In control cells, Pak-1 served as a functional inhibitor for MEKK-1, which inhibits the complex formation of MEKK-1 and p-JNK and thus inhibits the translocation of this complex into nucleus.Hence, we conclude that glioma cells utilize the availability of cytosolic p-JNK in driving the cells towards migration.
Affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.Show MeSH
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Mentions: Recent findings indicate that several targets of the JNK signaling pathway include a number of focal adhesion, microtubule-associated and intermediate filament proteins that are involved in cell migration (Bogoyevitch and Kobe, 2006; Huang et al., 2004b). In our study, we observed that the protein levels of the migratory motor molecules p-Paxillin, Vinculin, α-Actinin and Talin (Fig. 4a) and the adhesion molecules Integrin αvβ3 and Integrin β1 (Supplementary Fig. 5) also increased with radiation as compared to their matched non-irradiated counterparts. pUC treatment induced the translocation of p-JNK into the nucleus and therefore reduced the availability of cytosolic p-JNK in the cells treated with pUC and pUC + 10 Gy. Western blot analysis of 5310 and 4910 non-GICs and GICs revealed that the depletion of cytosolic p-JNK in the cells treated with pUC alone or in combination with radiation reduced the expression levels of the aforementioned migratory motor molecules (Fig. 4A) and the adhesion molecules (Supplementary Fig. 5). Addition of JNK inhibitor SP600125 to cells treated with SV, DMSO, 10 Gy, FLU and FLC significantly decreased the protein expression levels of p-Paxillin, Vinculin, α-Actinin, and Talin when compared to that of their respective counterparts (Fig. 4B), indicating the importance of cytosolic p-JNK in regulating the migration of the cells.
Affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.