(A) PREX2 (blue) is a GTP/GDP exchange factor that activates a GTPase called RAC. PTEN (brown) is a lipid phosphatase that suppresses tumors by inhibiting PI3K signaling (not shown). The interaction of PREX2 and PTEN (via their DHPH and CAT domains respectively) suppresses the catalytic activity of both. (B) Cancer-associated mutations in PREX2 (or C-terminal truncation of PREX2, as shown here) do not interfere with its ability to activate RAC or its ability to inhibit PTEN. However, PTEN is unable to inhibit mutated PREX2. Therefore mutations in PREX2 can lead to cancer by increasing both RAC and PI3K signaling. PREX2: phosphatidylinositol-3,4,5-triphosphate-dependent RAC exchange factor 2. PTEN: phosphatase and tensin homolog. RAC: RAS-related C3 botulinum toxin substrate.