Growth Regulation Cdc42 Targets Vesicle Transport

The mechanisms by which the GTP-binding protein Cdc42 induces cell transformation have not been clear. It now appears that Cdc42 regulates vesicle traffic through the Golgi, which may account for some of its growth-transforming activity. Wu et al. report that the GTP-bound form of a constitutively active Cdc42 mutant binds to the -subunit (COP) of a protein complex (COPI) that coats membrane regions that bud and form vesicles. Expression of this mutant appears to block intracellular transport of a transmembrane protein. However, expression of a constitutively active Cdc42 mutant that still retains GTPase activity and that also binds to COP accelerated intracellular transport and caused cell transformation, indicating that nucleotide cycling is critical for regulation of transport by Cdc42. If binding of this mutant to COP was inhibited, this mutant no longer transformed cells. The authors propose that the ability of Cdc42 to bind to COP is necessary for Cdc42-induced malignancy. Altered trafficking of proteins through the Golgi may be an important step in the growth transformation process. Cdc42, which predominantly localizes to the Golgi, may compete with cargo proteins for binding COP. GTP hydrolysis would then facilitate release of COP and allow COPI to stimulate vesicle movement.

Wu, W.J., Erickson, J.W., Lin, R., and Cerione, R.A. (2000) The -subunit of the coatamer complex binds to Cdc42 to mediate transformation. Nature 405: 800-804. [Online Journal]