Gene Section Review Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) 239 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) Max Cayo, David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert Chen Endocrine Cancer Disease Group, University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA Published in Atlas Database: March 2007 Online updated version: http://AtlasGeneticsOncology.org/Genes/RAF1ID42032ch3p25.html DOI: 10.4267/2042/38452 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Hugo: RAF1 Other names: CRAF; Raf-1; c-Raf Location: 3p25 DNA/RNA Note: History and Nomenclature: c-Raf-1 was the first successfully cloned functional human homolog of the v-Raf gene, and thus the gene product of c-Raf-1 has historically been referred to in the literature simply as Raf-1. Subsequently, B-Raf and A-Raf-1 paralogues (BRAF, located in Xq13 and ARAF, located in Xp11) were discovered. A suitable nomenclature is as follows: A-RAF, B-RAF, and C- RAF for the functional human proteins and A-RAF, B- RAF, and C-RAF for the corresponding genes; a-raf, b- raf, and c-raf for the murine proteins and A-Raf, B-Raf, and C-Raf for the corresponding genes. Raf-1 (or RAF- 1) is generally taken to mean C-RAF-1 but could apply to A-RAF-1 equally. Here, RAF-1 will be taken to mean C-RAF-1 (RAF-1 = C-RAF-1, etc.). Description C-RAF (RAF-1, C-RAF-1) encompasses 80,570 bp of DNA; 17 Exons. Transcription RAF-1 transcribed mRNA contains 3212-3216 nucleotides. Protein Description The RAF proteins share three conserved domains: two (CR1 and CR2) in the N terminus and a third (CR3- encoding for the serine/threonine kinase domain) in the C terminus. The RAF proteins exhibit complex regulation involving numerous phosphorylation sites throughout the proteins. Despite constitutional similarity, the Raf isoforms have been shown to carry out non-redundant functions, implying that they are distinct. RAF-1 (C-RAF-1): 72-74 kDa. Note: A-RAF: about 68 kDa. Note: B-RAF (which undergoes alternate splicing): ranges from 75 to 100 kDa. Expression C-RAF (RAF-1) and A-RAF mRNA is expressed ubiquitously. A-RAF mRNA is highly expressed in urogenital organs. B-RAF is expressed in a wide range of tissues, but most substantially in neuronal tissues. Localisation Cytosolic. Function RAF proteins are part of the conserved MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling cascade between the cell surface and the nucleus. RAF is regulated by the upstream RAS family of small G proteins. RAS is predominantly located on the inner leaflet of the plasma membrane and is functionally activated by GTP- binding. Binding of various extracellular ligands such as growth factors and hormones activates RAS and subsequently RAF proteins. RAS binds directly to the N-terminal regulatory domain or RAF (the RAS binding domain (RBD)). RAS interacts secondarily with the cysteine-rich domain (CRD) on CR1 of RAF. RAS-RAF binding can be affected by 14-3-3 proteins and other scaffold/adaptor proteins kinase suppressor of