CELL BIOLOGY Differential Rac Activation by Ras Isoforms

Abstract:

As mature as the field of Ras research is, interesting findings continue without abatement. The three isoforms of Ras, c-H-Ras, c-K-Ras, and c-N-Ras, share very high sequence identity except for their COOH-terminal hypervariable domains. Although little is known about the specific roles played by each isoform, some light is beginning to be shed on their functions. Walsh and Bar-Sagi have observed that c-H-Ras and c-K-Ras differ in their ability to activate Rac-dependent effects. By expressing constitutively activated forms of c-H-Ras and c-K-Ras (c-H-RasV12 and c-K-RasV12) in cells, the authors observed that c-K-RasV12-dependent membrane ruffles were highly convoluted and underwent marked changes in appearance, whereas the morphology of the c-H-RasV12-dependent ruffles did not change greatly. Additionally, cells expressing c-K-RasV12 exhibited greater motility. These effects correlated with enhanced activation of Rac by c-K-Ras in COS cells. Cells expressing chimeric proteins consisting of c-H-RasV12 except that the last 25 residues were from the c-K-Ras COOH-terminus exhibited similar characteristics (including the same subcellular distribution) as those cells expressing full-length c-K-RasV12. This indicates that the difference in the ability of c-H-Ras and c-K-Ras to activate Rac-dependent functions was mediated by the COOH-terminus of c-K-Ras, which includes a stretch of lysine residues not found in c-H-Ras. Thus, some of the different biological functions of Ras proteins may be imparted by their hypervariable COOH-termini.

A. B. Walsh, D. Bar-Sagi, Differential activation of the Rac pathway by Ha-Ras and K-Ras. J. Biol. Chem. 276, 15609-15615 (2001). [Abstract] [Full Text]