Glycogen Synthase Kinase 3 and h-prune Regulate Cell Migration by Modulating Focal Adhesions

Abstract

h-prune, which has been suggested to be involved in cell migration, was identified as a glycogen synthase kinase 3 (GSK-3)-binding protein. Treatment of cultured cells with GSK-3 inhibitors or small interfering RNA (siRNA) for GSK-3 and h-prune inhibited their motility. The kinase activity of GSK-3 was required for the interaction of GSK-3 with h-prune. h-prune was localized to focal adhesions, and the siRNA for GSK-3 or h-prune delayed the disassembly of paxillin. The tyrosine phosphorylation of focal adhesion kinase (FAK) and the activation of Rac were suppressed in GSK-3 or h-prune knocked-down cells. GSK-3 inhibitors suppressed the disassembly of paxillin and the activation of FAK and Rac. Furthermore, h-prune was highly expressed in colorectal and pancreatic cancers, and the positivity of the h-prune expression was correlated with tumor invasion. These results suggest that GSK-3 and h-prune cooperatively regulate the disassembly of focal adhesions to promote cell migration and that h-prune is useful as a marker for tumor aggressiveness.

Supplemental material for this article may be found at http://mcb.asm.org/.

We are grateful to K. Matsumoto, S. Takada, J. R. Woodgett, Y. Matsuura, H. Sabe, K. Kaibuchi, and M. D. Schaller for donating cells, plasmids, and baculoviruses.

This work was supported by Grants-in-Aid for Scientific Research and for Scientific Research on Priority Areas from the Ministry of Education, Science, and Culture, Japan (2002, 2003, 2004, 2005); by grants from the Yamanouchi Foundation for Research on Metabolic Disorders (2003) and the Sankyo Foundation of Life Science (2004, 2005); and by grants from EU FP6-BRECOSM-LSH-CT-503234 (M.Z.).