Gene Summary: HRAS gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These hras proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This hras protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this HRAS gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, mental retardation, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this HRAS gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this HRAS gene. [provided by RefSeq, Jul 2008]General information above from NCBI
Enzyme regulation: Alternate between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase- activating protein (GAP).
Subunit structure: In its GTP-bound form interacts with PLCE1. Interacts with TBC1D10C. Interacts with RGL3. Interacts with HSPD1. Found in a complex with at least BRAF, HRAS1, MAP2K1, MAPK3 and RGS14. Interacts (active GTP-bound form) with RGS14 (via RBD 1 domain) (By similarity). Forms a signaling complex with RASGRP1 and DGKZ. Interacts with RASSF5. Interacts with PDE6D. Interacts with IKZF3. Interacts with GNB2L1. Interacts with PIK3CG; the interaction is required for membrane recruitment and beta-gamma G protein dimer- dependent activation of the PI3K gamma complex PIK3CG:PIK3R6 (By similarity).
Subcellular location: Cell membrane. Cell membrane; Lipid-anchor; Cytoplasmic side. Golgi apparatus. Golgi apparatus membrane; Lipid-anchor. Note=The active GTP-bound form is localized most strongly to membranes than the inactive GDP-bound form (By similarity). Shuttles between the plasma membrane and the Golgi apparatus.
Isoform 2: Nucleus. Cytoplasm. Cytoplasm, perinuclear region. Note=Colocalizes with GNB2L1 to the perinuclear region.
Tissue specificity: Widely expressed.
Post-translational: Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi.
S-nitrosylated; critical for redox regulation. Important for stimulating guanine nucleotide exchange. No structural perturbation on nitrosylation.
The covalent modification of cysteine by 15-deoxy-Delta12,14- prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S- nitrosylation and S-palmitoylation.
Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs) (By similarity).
Involvement in disease: Faciocutaneoskeletal syndrome (FCSS) [MIM:218040]: A rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities. Note=The disease is caused by mutations affecting the gene represented in this entry.
Congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]: Variant of Costello syndrome. Note=The disease is caused by mutations affecting the gene represented in this entry.
Hurthle cell thyroid carcinoma (HCTC) [MIM:607464]: A rare type of thyroid cancer accounting for only about 3-10% of all differentiated thyroid cancers. These neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
Note=Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors.
Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
Note=Defects in HRAS are the cause of oral squamous cell carcinoma (OSCC).
Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:163200]: A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis. Note=The disease is caused by mutations affecting the gene represented in this entry.
Sequence similarity: Belongs to the small GTPase superfamily. Ras family.
General information above from UniProt