KRAS4A

KRAS4A is one of two major protein isoforms produced by alternative splicing of the KRAS gene in humans. The two splice variants, KRAS4A and KRAS4B, share the N-terminal region and the GTPase domain but differ in their C-terminal hypervariable region due to the inclusion of alternative exon 4A or exon 4B. The KRAS gene is located on chromosome 12p12.1 and encodes a member of the Ras family of small GTPases that function as molecular switches in signal transduction.

Like other Ras proteins, KRAS4A cycles between GDP-bound inactive and GTP-bound active states. Activation is driven by guanine nucleotide exchange factors such as SOS1 and inactivation by GTPase-activating proteins; active KRAS4A engages downstream effectors including RAF kinases, PI3K, and RalGDS to regulate cell proliferation, differentiation and survival. Signaling output is influenced by the subcellular localization of KRAS4A at the plasma membrane and other intracellular membranes, which is determined in part by lipid modifications.

KRAS4A and KRAS4B differ in their C-terminal lipid modifications, which influence membrane association and signaling. KRAS4B is anchored mainly by a farnesyl group and a polybasic region, while KRAS4A can undergo both farnesylation and palmitoylation, leading to distinct membrane targeting and trafficking patterns that can affect effector interactions and regulatory protein binding.

KRAS4A is expressed in many tissues but generally at lower levels than KRAS4B, with tissue- and development-specific variation. In cancer, activating mutations in KRAS that impair GTP hydrolysis are among the most common oncogenic alterations, driving aberrant signaling in pancreatic, colorectal, and lung cancers; these mutations affect the KRAS protein regardless of splice variant. Researchers continue to study potential isoform-specific roles of KRAS4A in normal physiology and oncogenesis.