| KRAS belongs to the Ras family of small GTPases alongside HRAS and NRAS, cycling between GTP-bound active and GDP-bound inactive states to transduce growth factor signals from receptor tyrosine kinases into intracellular cascades regulating proliferation, survival, and differentiation. KRAS organizes a core G domain for nucleotide binding and hydrolysis with switch I/II regions that undergo conformational shifts upon GTP loading, alongside a hypervariable C-terminus featuring a farnesyl cysteine for membrane anchoring via CAAX motif processing. Oncogenic mutations at G12, G13, or Q61 impair GTPase activity by sterically blocking GAP-mediated arginine finger insertion into the active site, locking KRAS in the GTP conformation that constitutively recruits RAF kinases through switch I effector binding while allosterically engaging PI3K at switch II to activate AKT-mTOR signaling for anabolic metabolism. GTP-KRAS dimers form nanoclusters at the plasma membrane that amplify RAF dimerization and MEK-ERK phosphorylation cascades culminating in MYC and cyclin D1 transcription for G1/S progression, while parallel PI3K pathway activation sustains FOXO exclusion and BCL2 upregulation to evade apoptosis. In physiological contexts, KRAS calibrates lung alveolar development and pancreatic acinar regeneration through precise spatial-temporal activation tuned by SOS GEFs and NF1 GAPs responding to EGFR gradients. Mutant KRAS drives nearly universal pancreatic ductal adenocarcinoma initiation alongside frequent colorectal and lung cancers through autocrine loops sustaining RAF and PI3K outputs despite upstream inhibition. |
Lane 1: Hela, Lane 2: 22Rv1, Lane 3: SW480
