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• _7 value "as shown in Figure 2.95-98 In essence, the activation status of Raf depends on the integration of both activating and inhibitory stimuli, the net result of which determines the downstream messages. THE RAF FAMILY OF GENES AND PROTEINS The raf family of genes was first identified as oncogenes in retroviruses that are the causative vectors of tumors in mice and chicken.99,100 The first raf gene to be identified, v-raf, the transforming gene of the mouse sarcoma virus 3611, induces fibrosarcomas and erythroleukemia in newborn mice, and C-raf (also called raf-1) is its proto-oncogene homolog.101,102 A-raf was found next by screening a mouse spleen cDNA library at low stringency with a v-raf probe. Next, v-Rmil was identified as the transforming gene in the avian retrovirus Mill Hill No. 2 (MH2) from a spontaneous ovarian tumor and found to be homologous to v-raf.99 C-Rmil corresponded to a third mammalian raf gene, B-raf, which was also shown to be an oncogene.103,104 However, initial attempts to identify activated versions of raf in human cancers failed to demonstrate unique DNA rearrangements in any specific tumor type, which, in retrospect, can be attributed to the lack of requisite sensitivity of early assays to detect single point mutations. Furthermore, most early efforts were directed at C-raf, rather than at the more oncogenic B-raf. The mammalian raf family consists of the following three genes: A-raf, B-raf, and C-raf, which are located on chromosomes Xp11, 7q32, and 3p25, respectively. The raf proto-oncogenes encode three 68- to 74-kd cytosolic proteins, termed A-Raf, B-Raf, and C-Raf (Raf-1), which share highly conserved amino-terminal regulatory regions and catalytic domains at the carboxyl terminus (Fig 4).10 As serine/threonine kinases, Raf proteins phosphorylate serine and threonine residues on essential modulatory proteins downstream of Ras. Each Raf species has a distinct expression profile in tissues, which suggests that individual Raf isoforms perform clearly defined functions.4 C-Raf is ubiquitously expressed in most tissues. Both A- and B-Raf have more restricted expression profiles than C-Raf, with A-Raf overexpressed in urogenital tissues (eg, kidney, ovary, prostate, and epididymis) and B-Raf overexpressed in neural, testicular, splenic, and hematopoietic tissues.105 Unlike A-raf and C-raf, B-raf undergoes differential splicing in exons 8b and 10a, and its spliced variants are translated into 10 B-Raf isoforms.106,107 Both A-Raf and C-Raf undergo localization to the mitochondria, which supports the notion that Raf regulates apoptosis, but the specific proportions of Raf isoforms that are localized to the mitochondria are not known.108-112 This localization may be a result of isoform-specific lipid- or protein-binding partners, which recruit Raf to distinct membrane rafts. From a functional standpoint, although all Raf proteins are serine/threonine kinases and capable of activating the MAPK cascade, they have distinct downstream phosphorylation targets and play unique roles in signaling.113 Their distinct roles are supported by Raf knockout studies, in which mice lacking each of the three Raf proteins have disparate phenotypes.113,114 B-raf knockouts die in utero by day 12, usually as a result of massive internal hemorrhage, whereas A-raf and C-raf knockouts die postpartum with extensive intestinal distension (A-raf knockout) or failure of lung maturation (C-raf knockout). Additional support for the diverse functionality of Raf family members is provided by the disparate responses of B-Raf and C-Raf to identical stimuli, as well as the distinct messages that each isoform relays downstream to Rap1, which is a small GTPase that functions as both an activator and repressor of Raf.115 For example, Rap1- mediated stimulation of B-Raf by cyclic adenosine monophosphate (cAMP) phosphorylates ERK, whereas stimulation of C-Raf inhibits ERK phosphorylation.115" provenance.