Ras processing and trafficking to subcellular compartments. H-Ras, N-Ras, K-Ras4a, and K-Ras4b proteins are identical in the first 85 amino acids, a region that includes the P loop (phosphate binding loop, amino acids 10-16), which binds the γ-phosphate of GTP, and the switch I (amino acids 30-38) and switch II (amino acids 60-76) regions, which regulate binding to Ras regulators and effectors. The next 78 amino acids show ∼ 85%-90% sequence homology. Amino acids that are shared by all isoforms are depicted in light gray, those that differ are depicted in dark gray. The final 24 (23 for K-Ras4b) amino acids, called the hypervariable region (HVR), specify posttranslational modifications and trafficking for each Ras isoform. All 4 isoforms have a C-terminal —CAAX motif, which is farnesylated (F) by FTase. The —AAX is removed by Ras-converting enzyme 1 (RCE1) and the cysteine methylated (M) by ICMT. K-Ras4b is then shuttled directly to the PM where it is stabilized by its polylysine domain (KKKKKK). The other 3 isoforms are shuttled to the Golgi apparatus, where they are palmitoylated (P) at one or more cysteines near the C-terminus before reaching the plasma membrane. On the membrane, H-Ras, N-Ras, and K-Ras4a can be depalmitoylated by acyl protein thioesterases 1 and 2 (APT1/APT2), directing them back to the Golgi. This palmitoylation-depalmitoylation, Golgi-plasma membrane cycle continues in a delicate balance until the proteins are degraded.