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Link to original content: https://omim.org/entry/311010
Alternative titles; symbols
HGNC Approved Gene Symbol: ARAF
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38) : X:47,561,205-47,571,908 (from NCBI)
By screening a fetal liver cDNA library at reduced stringency for v-raf-related sequences, Mark et al. (1986) found a sequence in addition to the expected RAF1 (164760). This sequence, which they called PKS (presumably for 'protein kinase sequence'), showed 71% nucleotide homology to RAF1. The predicted amino acid sequence of the kinase domain was sufficiently like the sequence of v-raf to suggest that PKS may encode a polypeptide with serine/threonine kinase activity. Mark et al. (1986) found that expression of PKS mRNA (2.7 kb) was elevated in peripheral blood mononuclear cells isolated from 2 patients with angioimmunoblastic lymphadenopathy with dysproteinemia, a disease in which autoantibodies are produced following the lymphoproliferative activation of B cells.
By screening a mouse cDNA library with a v-raf oncogene probe, Huebner et al. (1986) also isolated a transforming raf-related cDNA, A-raf, that represented a gene distinct from RAF1. As an initial step in the analysis of this RAF1-related cDNA, they isolated a human ARAF cDNA and used it to map the genes in mouse and man.
Beck et al. (1987) deduced the complete 606-amino acid sequence of the human ARAF1 oncogene from the 2,453-nucleotide sequence of the cDNA.
Yuryev et al. (2000) stated that ARAF contains an N-terminal regulatory domain and a C-terminal catalytic domain. The regulatory domain contains a RAS (HRAS; 190020)-binding domain and a cysteine-rich domain. Immunohistochemical analysis and immunoelectron microscopy of fractionated rat liver revealed that a portion of Araf localized to mitochondria.
Because of an 80% homology to RAF1 in its kinase domain, Huebner et al. (1986) speculated that the ARAF1 gene product may have serine/threonine-specific kinase activity.
The RAF protooncogenes encode cytoplasmic protein serine/threonine kinases that play a critical role in cell growth and development. Araf1 in the mouse is expressed predominantly in urogenital tissues (Lee et al., 1994).
Pelkmans and Zerial (2005) explored the role of some kinases in caveolae dynamics. Using RNAi, they identified functions at distinct steps of the caveolar cycle. In the first step, the silencing of ARAF1, a serine/threonine kinase involved in mitogenic signaling, resulted in diffuse CAV1 (601047)-GFP staining that was laterally mobile, in addition to the characteristic spot-like pattern. The authors suggested that in the absence of ARAF1, the caveolar coat is less stable or inefficiently assembled. Their observations revealed new principles in caveolae trafficking and suggested that the dynamic properties of caveolae and their transport competence are regulated by different kinases operating at several levels.
Using yeast 2-hybrid analysis of HeLa cells, Yuryev et al. (2000) showed that the N-terminal regulatory domain of ARAF interacted with the putative mitochondrial proteins TOM (PPRF6; 613979) and TIM44 (TIMM44; 605058).
Lee et al. (1994) demonstrated that the ARAF1 gene in the human comprises 16 exons encoded by a minimum of 10,776 nucleotides.
Huebner et al. (1986) used a human ARAF cDNA to map the genes in mouse and man. The mouse gene cosegregated with the X chromosome in Chinese hamster-mouse hybrid cells. In humans, 2 independently segregating loci, designated ARAF1 and ARAF2, were mapped to chromosomes X and 7, respectively. (Huebner et al. (1986) had not conclusively shown that the ARAF2 locus on chromosome 7 is transcribed, and indeed the ARAF2 locus, now designated ARAF2P, has been shown to be a pseudogene (Lee et al., 1994).) The single X-linked ARAF locus of the mouse and the ARAF1 locus of man are actively transcribed in several mouse and human cell lines. By in situ hybridization, Huebner et al. (1986) mapped the ARAF1 gene to Xp21-q11, with most grains at Xp13-p11. Popescu and Mark (1989) regionalized the gene to Xp11.4-p11.2 by in situ hybridization.
Avner et al. (1987) found that in the mouse the A-raf oncogene is on the X chromosome, 10 to 17 cM proximal to the Hprt gene. The localization was considered compatible with the presence of the ARAF oncogene on the short arm of the X chromosome between the centromere and Xp21 in man.
Avner, P., Bucan, M., Arnaud, D., Lehrach, H., Rapp, U. A-raf oncogene localizes on mouse X chromosome to region some 10-17 centimorgans proximal to hypoxanthine phosphoribosyltransferase gene. Somat. Cell Molec. Genet. 13: 267-272, 1987. [PubMed: 3299748] [Full Text: https://doi.org/10.1007/BF01535208]
Beck, T. W., Huleihel, M., Gunnell, M., Bonner, T. I., Rapp, U. R. The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nucleic Acids Res. 15: 595-609, 1987. [PubMed: 3029685] [Full Text: https://doi.org/10.1093/nar/15.2.595]
Huebner, K., ar-Rushdi, A., Griffin, C. A., Isobe, M., Kozak, C., Emanuel, B. S., Nagarajan, L., Cleveland, J. L., Bonner, T. I., Goldsborough, M. D., Croce, C. M., Rapp, U. Actively transcribed genes in the raf oncogene group, located on the X chromosome in mouse and human. Proc. Nat. Acad. Sci. 83: 3934-3938, 1986. [PubMed: 3520560] [Full Text: https://doi.org/10.1073/pnas.83.11.3934]
Lee, J.-E., Beck, T. W., Brennscheidt, U., DeGennaro, L. J., Rapp, U. R. The complete sequence and promoter activity of the human A-raf-1 gene (ARAF1). Genomics 20: 43-55, 1994. [PubMed: 8020955] [Full Text: https://doi.org/10.1006/geno.1994.1125]
Mark, G. E., Seeley, T. W., Shows, T. B., Mountz, J. D. Pks, a raf-related sequence in humans. Proc. Nat. Acad. Sci. 83: 6312-6316, 1986. [PubMed: 3529082] [Full Text: https://doi.org/10.1073/pnas.83.17.6312]
Pelkmans, L., Zerial, M. Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436: 128-133, 2005. [PubMed: 16001074] [Full Text: https://doi.org/10.1038/nature03866]
Popescu, N. C., Mark, G. E. Localization of the pKs gene, a raf related sequence on human chromosomes X and 7. Oncogene 4: 517-519, 1989. [PubMed: 2717185]
Yuryev, A., Ono, M., Goff, S. A., Macaluso, F., Wennogle, L. P. Isoform-specific localization of A-RAF in mitochondria. Molec. Cell. Biol. 20: 4870-4878, 2000. [PubMed: 10848612] [Full Text: https://doi.org/10.1128/MCB.20.13.4870-4878.2000]