Inhibition of GTPase Activating Protein Stimulation of Ras-p21 GTPase by the K <i>rev</i> -1 Gene Product

TLDR

Krev‑1 suppresses ras‑mediated transformation, yet the mechanism is unclear; its product Rap1A‑p21 shares the GAP‑binding region of Ras‑p21. The study tested whether GAP can interact with Rap1A‑p21. Rap1A‑p21 binds GTP‑dependent GAP tightly, competitively inhibiting GAP‑mediated Ras‑GTPase activity, and may explain Krev‑1’s suppression of ras transformation by blocking GAP interactions.

Abstract

Krev-1 is known to suppress transformation by ras. However, the mechanism of the suppression is unclear. The protein product of Krev-1, Rap1A-p21, is identical to Ras-p21 proteins in the region where interaction with guanosine triphosphatase (GTPase) activating protein (GAP) is believed to occur. Therefore, the ability of GAP to interact with Rap1A-p21 was tested. Rap1A-p21 was not activated by GAP but bound tightly to GAP and was an effective competitive inhibitor of GAP-mediated Ras-GTPase activity. Binding of GAP to Rap1A-p21 was strictly guanosine triphosphate (GTP)-dependent. The ability of Rap1A-p21 to bind tightly to GAP may account for Krev-1 suppression of transformation by ras. This may occur by preventing interaction of GAP with Ras-p21 or with other cellular proteins necessary for GAP-mediated Ras GTPase activity.