DIRAS3 Gene - Function, Mutations, and Role in Cancer | NCBI, UniProt, OMIM

DIRAS3 (DIRAS family GTPase 3), also known as ARHI (Aplasia Ras homolog member I) or NOEY2, is an imprinted, maternally expressed tumor suppressor gene located on chromosome 1p31.3. It encodes a 26 kDa GTPase protein belonging to the Ras superfamily. DIRAS3 is frequently downregulated or silenced by promoter hypermethylation in various cancers, including ovarian, breast, and lung cancers. The protein inhibits cell proliferation, induces autophagy, and promotes apoptosis through multiple signaling pathways, including PI3K/AKT and MAPK. Loss of DIRAS3 expression is associated with poor prognosis in several malignancies.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• PI3K/AKT signaling pathway

• MAPK signaling pathway

• Autophagy pathway

• Apoptosis signaling pathway

• Ras signaling pathway

DIRAS3 is a 26 kDa GTPase protein with structural similarity to Ras but functions as a tumor suppressor. It localizes to the plasma membrane and endomembranes, where it cycles between active GTP-bound and inactive GDP-bound states. Unlike classical Ras oncoproteins, DIRAS3 lacks transforming activity and instead inhibits cell growth by blocking PI3K/AKT and MAPK signaling, inducing G1 cell cycle arrest, and promoting autophagy and apoptosis. The protein is imprinted and expressed only from the maternal allele; loss of expression through promoter hypermethylation or LOH is a common event in multiple cancers. Re-expression of DIRAS3 in cancer cells suppresses tumor growth and enhances sensitivity to chemotherapy.