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• _6 value "The Structure of Raf The structure of Raf consists of the following: (1) an amino terminus that contains the regulatory domain; (2) an activation loop; and (3) a carboxyl terminus that contains the kinase domain116-118 (Fig 4). All Raf kinases are composed of three conserved regions, CR1 (adjacent to the amino terminus), CR2, and CR3 (adjacent to the carboxyl terminus). The regulation of Raf kinase activity is a complex process involving phosphorylation of the regulatory and catalytic domains of the protein and both inter- and intramolecular interactions. The initial process of Raf activation involves the interaction of active GTP-bound Ras with the RBD of Raf and the adjacent zinc-binding cysteine-rich domain (CRD) of CR1, facilitating recruitment of Raf to the cell membrane for activation.78 The role of CR2, which is rich in serine and threonine residues, is less well defined; however, the phosphorylation of moieities within CR2 and various proteinprotein interactions involving CR2 also affect Raf localization and activation.89,119-121 Deletions of the amino-terminal regulatory domains CR1 and CR2, similar to v-Raf, are found in several types of human cancers with activating Raf mutations, suggesting that these domains negatively regulate Raf function. CR3, the catalytic domain of Raf, is also subject to regulation by phosphorylation. Regulation of Raf Kinase Activity General. The overlapping functional aspects of the three Raf isoforms have been elucidated by studies involving Raf knockout mice. In C-Raf knockouts, B-Raf can compensate for the loss of C-Raf in activating MEK in the MAPK pathway, but C-Raf knockouts are much more susceptible to apoptotic stimuli, despite the presence of A-Raf and B-Raf.122 With regard to differences in signaling between the Raf isoforms, A-Raf is a weaker activator of MEK than B-Raf or C-Raf. Furthermore, A-Raf can activate MEK1 only, whereas C-Raf activates both MEK1 and MEK2.123-125" provenance.
• _6 wasQuotedFrom 16170185 provenance.