Ras

**Structure and function** - Ras is a small monomeric GTPase (~21 kDa) anchored to the inner plasma membrane by farnesylation (a lipid modification). - It works as a molecular switch. GDP-bound Ras is inactive. GTP-bound Ras is active. - GEFs (guanine nucleotide exchange factors, e.g., SOS) load GTP and activate Ras. GAPs (GTPase-activating proteins, e.g., neurofibromin/NF1) enhance Ras's intrinsic GTPase activity, hydrolyze GTP to GDP, and turn Ras off.

**Signaling pathway** - A growth factor (EGF, PDGF, etc.) binds a receptor tyrosine kinase (RTK), which autophosphorylates. - The adaptor Grb2 binds the phosphorylated receptor and recruits SOS (GEF). - SOS activates Ras by exchanging GDP for GTP. - Ras-GTP activates Raf (MAP3K), which phosphorylates MEK (MAP2K), which phosphorylates ERK (MAPK). - ERK enters the nucleus and activates transcription factors (Myc, Fos/Jun), which promote cell cycle progression (cyclin D) and proliferation. - Ras also activates PI3K–Akt–mTOR (survival, growth).

**Oncogenesis** - Point mutations (classically codon 12, 13, or 61) abolish GTPase activity or GAP responsiveness. Ras stays locked in the GTP-bound state, causing constitutive proliferative signaling. This is a gain-of-function mutation in a proto-oncogene. - KRAS is the most commonly mutated isoform overall, in pancreatic ductal adenocarcinoma (~90%), colorectal cancer (~40%), and lung adenocarcinoma. - HRAS is associated with bladder cancer and Costello syndrome (germline). - NRAS is associated with melanoma and some hematologic malignancies (e.g., AML, myeloma). - Loss of the GAP NF1 (neurofibromatosis type 1) causes unchecked Ras activity, giving neurofibromas, café-au-lait spots, and Lisch nodules.

**Clinical pearls** - KRAS-mutant colorectal cancers do not respond to anti-EGFR antibodies (cetuximab, panitumumab) because the signal is constitutively active downstream of the receptor. Test KRAS/NRAS before using them. - BRAF V600E (downstream of Ras) occurs in melanoma and is treated with vemurafenib or dabrafenib. Hairy cell leukemia also carries BRAF V600E. - Newer KRAS G12C inhibitors (sotorasib, adagrasib) are used in KRAS G12C-mutant non-small cell lung cancer. - Farnesyltransferase inhibitors were developed to block Ras membrane localization but have limited clinical success. - RASopathies (germline Ras–MAPK pathway mutations) include Noonan, Costello, and cardiofaciocutaneous syndromes. - Mnemonic: Ras = "RAS is a Real Accelerator Stuck on" when mutated. It is a proto-oncogene, and a single mutated allele is sufficient (dominant).

**Related concepts** - Proto-oncogene vs. tumor suppressor: Ras is a proto-oncogene (gain-of-function). p53 and Rb are tumor suppressors (loss-of-function, two-hit). - Other G proteins (heterotrimeric Gs, Gi, Gq) are distinct from small monomeric GTPases like Ras, though both use GTP/GDP cycling.