|Permanent link:||http://hdl.handle.net/10197/5569||Date:||6-Apr-2010||Abstract:||A-Raf (v-raf murine sarcoma 3611 viral oncogene homolog) is a serine/threonine protein kinase of the Raf family that comprises A-Raf, B-Raf and C-Raf. Raf kinases are at the apex of the three-tiered Raf-MEK-ERK/MAPK pathway that features over 150 substrates and regulates many fundamental cellular functions, including proliferation, differentiation, transformation, apoptosis and metabolism. The only commonly accepted substrates for all three Raf kinases are MEK1/2, a pair of dual-specificity kinases that have ERK1/2 as substrates. A-Raf is the least studied member of the Raf family. A-Raf seems to be regulated similarly to C-Raf, with binding to activated Ras initiating the growth-factor-induced activation of A-Raf. In addition, A-Raf activity is regulated by phosphorylation, lipid interactions and protein-protein interactions. For instance, binding of the regulatory subunit of casein kinase II, CK2β, was shown to enhance A-Raf kinase activity. However, A-Raf is a poor MEK kinase with barely measurable catalytic activity, suggesting that A-Raf could have functions outside the MAPK cascade. A-Raf binding to mitochondrial membrane proteins suggests a potential role in mitochondrial transport and anti-apoptotic signaling pathways. Furthermore, the association of A-Raf with the pyruvate kinase M2, M2-PK, causing dimerization and inactivation of M2-PK, may link A-Raf signaling with energy metabolism and the Warburg effect in tumor cells. The generation of A-Raf knock-out mice revealed a role in neuronal migration and development. Recently, alternative A-Raf splice forms encoding truncated A-Raf proteins were identified. Owing to their ability to bind and block activated Ras, they function as physiological dominant-negative Ras inhibitors with roles in differentiation and transformation. A-Raf is expressed in most tissues, but expression levels differ dramatically. Elevated levels were reported in a number of malignancies, although no oncogenic mutations have been found.||Type of material:||Journal Article||Publisher:||Nature Publishing Group||Copyright (published version):||2010 Nature Publishing Group||Keywords:||A-RAF;A-Raf;A-raf;ARAF;Araf;Araf1;ARAF1;PKS2;kinase sequence;RAFA1;v-raf murine sarcoma 3611 viral oncogene homolog||DOI:||10.1038/mp.a000307.01||Language:||en||Status of Item:||Peer reviewed|
|Appears in Collections:||Conway Institute Research Collection|
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