HRAS

HRAS is a gene that encodes HRas, a member of the Ras family of small GTPases. The HRAS gene is located on chromosome 11p15.5 and produces a protein of about 189 amino acids with a molecular weight near 21 kDa. HRas functions as a molecular switch in intracellular signaling: it cycles between an inactive GDP-bound form and an active GTP-bound form. This cycling is regulated by guanine nucleotide exchange factors (GEFs) such as SOS and GTPase-activating proteins (GAPs) such as NF1. In its active state, HRas engages downstream effectors, notably the RAF kinase family to activate the MAPK/ERK pathway, and it can also influence the PI3K-AKT and RalGEF pathways, thereby affecting cell proliferation, differentiation, survival, and cytoskeletal organization. Post-translational lipid modifications, including farnesylation at the C-terminus CaaX motif and proximal palmitoylation, promote the protein’s association with the inner surface of the plasma membrane where signaling occurs.

Clinically, HRAS is a proto-oncogene. Somatic activating mutations in HRAS occur in a subset of cancers, with hotspots at codons such as 12 and 61. These mutations lead to constitutive signaling and contribute to oncogenesis in tumor types including bladder urothelial carcinoma, thyroid cancers, and head and neck cancers, among others. HRAS was one of the first Ras family genes identified as an oncogene, named after the Harvey sarcoma virus, and it remains a key model for studying GTPase signaling and targeted cancer therapy research.