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Luo, Z.; , . Role of Raf Family in Biology. Encyclopedia. Available online: https://encyclopedia.pub/entry/23103 (accessed on 15 June 2024).
Luo Z,  . Role of Raf Family in Biology. Encyclopedia. Available at: https://encyclopedia.pub/entry/23103. Accessed June 15, 2024.
Luo, Zhijun, . "Role of Raf Family in Biology" Encyclopedia, https://encyclopedia.pub/entry/23103 (accessed June 15, 2024).
Luo, Z., & , . (2022, May 19). Role of Raf Family in Biology. In Encyclopedia. https://encyclopedia.pub/entry/23103
Luo, Zhijun and . "Role of Raf Family in Biology." Encyclopedia. Web. 19 May, 2022.
Role of Raf Family in Biology
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The Raf kinase family consists of three isoforms, C-Raf/Raf-1, B-Raf and A-Raf. They are located directly downstream of Ras and upstream of MEK1/2. Since the discovery of v-Ras, v-Raf and ERK and the connection of this regulatory hub with oncogenesis, tremendous efforts have been invested in the elucidation of the mechanisms underlying the activation of Raf kinases. The Raf/MEK/ERK pathway is the first and clearly defined mitogenic pathway whose signal is invoked by extracellular mitogenic ligands and serves as a framework for other MAPK pathways. Among three isoforms of the Raf family, B-Raf is the only one that has so far been found mutated in many types of cancers. As all of the Raf family members directly act downstream of Ras, C-Raf and A-Raf are also important factors contributing to oncogenesis, either mediating the effects of mutated Ras or participating in oncogenic B-Raf-mediated pathogenesis. Thus, the development of Raf inhibitors has been a focus in cancer therapy.

Raf MEK ERK oncogenes phosphorylation signal transduction growth control

1. Introduction

The Raf kinase family consists of three isoforms, C-Raf/Raf-1, B-Raf and A-Raf [1][2]. They are located directly downstream of Ras and upstream of MEK1/2 [3][4]. Since the discovery of v-Ras, v-Raf and ERK [5][6][7][8][9][10][11][12] and the connection of this regulatory hub with oncogenesis, tremendous efforts have been invested in the elucidation of the mechanisms underlying the activation of Raf kinases. The Raf/MEK/ERK pathway is the first and clearly defined mitogenic pathway whose signal is invoked by extracellular mitogenic ligands and serves as a framework for other MAPK pathways [13]. Among three isoforms of the Raf family, B-Raf is the only one that has so far been found mutated in many types of cancers [14]. As all of the Raf family members directly act downstream of Ras, C-Raf and A-Raf are also important factors contributing to oncogenesis, either mediating the effects of mutated Ras or participating in oncogenic B-Raf-mediated pathogenesis. Thus, the development of Raf inhibitors has been a focus in cancer therapy.
The Raf/MEK/ERK pathway plays important roles not only in physiological processes, including cell proliferation, differentiation and development, but also in oncogenesis and cancer progression [15]. The oncogenic Ras isoforms, KRas, HRas and NRas, whose mutations have been found in more than 30% of human cancers, as well as overexpression of growth factors and mutations of their receptors in human cancer, all lead to the activation of this pathway [11][12][16]. Furthermore, B-Raf mutations are present in approximately 8% of human cancers [17], including 50% of melanoma [14], 45% of papillary thyroid cancer [18], 10% of colon cancer [19], 10% of non-small cell lung cancer [20] and almost 100% of hairy cell leukemia cases [21]. Thus, the development of drugs targeting the Raf/MEK/ERK pathway is especially important for cancer therapy. To fulfill this objective, the elucidation of this pathway is a crucial step. Although the mechanisms of MEK and ERK activation are relatively straightforward, Raf activation is rather complex and still incompletely understood. Moreover, the discovery of homo- and hetero-dimerization of Raf isoforms adds to the complexity of deciphering the mechanism of their activation, which also makes the development of Raf inhibitors a challenging and daunting task. Therefore, this research will summarize current knowledge of the regulation of Raf isoforms and progress in the drug development of Raf inhibitors for cancer therapy.

2. Discovery of the Raf/MEK/ERK Pathway

In the early 1980s, v-Raf was initially identified as a transforming gene of the murine retrovirus 3611-murine sarcoma virus (MSV) [5][22]. In neonatal mice, it causes predominantly fibrosarcoma and erythroleukemias. Hence, the name of Raf originated from its capability to stimulate “Rapidly Accelerated Fibrosarcomas” [23]. Shortly after, the genome of the avian carcinoma virus MH2 was found to encode a closely related oncogene named v-mil [24]. Comparison of DNA sequences of these oncogenes coupled with biochemical studies has revealed that v-Raf and v-mil are retroviral oncogenes derived from cellular proto-oncogenes of mammalian and avian species. Both genes encode products that are classified into the serine/threonine kinase family, homologous to tyrosine specific SRC kinases in the kinase domain. v-Raf and v-mil are fused to the N-myristoylated (N-myr) viral Gag sequence but with the deletion of amino-terminal moieties, in contrast to their cellular counterparts [25][26].
The first cellular counterparts of v-Raf, C-Raf-1 and C-Raf-2, were cloned and sequenced in 1985. However, it soon became apparent that C-Raf-2 is a pseudogene. Thus, the C-Raf-1 gene product was designated as C-Raf. Studies have reported that C-Raf is located at human chromosomal band 3p25, consisting of nine exons that are similar to v-Raf and v-mil as well as two extra exons that are related to v-mil [27][28]. Later on, two more Raf family members, A-Raf and B-Raf, were identified in vertebrates [2][29][30]. Although C-Raf was the first to be discovered in mammals, the ortholog of B-Raf is D-Raf in Drosophila melanogaster and LIN-45 in Caenorhabditis elegans [31][32]. A-Raf is the smallest subtype with a molecular weight of 68 kDa, C-Raf having a weight of 73 kDa, while B-Raf ranges from 75 to 100 kDa, this being attributable to variable splicing [33][34].
The Human Protein Atlas expression database shows that C-Raf mRNA and A-Raf mRNA are predominantly present in skeletal muscle, bone marrow and the proximal digestive tract, while B-Raf mRNA is highly expressed in the retina, bone marrow and brain. Genetic and biochemical studies in C. elegans and D. melanogaster have demonstrated that Raf functions downstream of Ras and participates in cell proliferation, differentiation and development [31][32].
The mammalian mitogen-activated protein kinase (MAPK) was first identified in mammalian cells and then in yeast [35][36]. When adipocytes were briefly treated with insulin, a soluble serine/threonine kinase was rapidly activated, leading to increased phosphotyrosine content on microtubule-associated protein-2. Hence, it was initially named microtubule-associated protein-2 protein kinase (MAP-2 kinase). As it promotes cell cycle progression in response to insulin, growth factors and transforming proteins of oncogenic viruses, and phosphorylates a variety of protein substrates, it was renamed mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase (ERK) [35][37][38]. Two isoforms, ERK1 and ERK2, are encoded by the MAPK3 and MAPK1 genes, respectively. Activation of ERK1/2 requires phosphorylation at threonine and tyrosine residues and inactivation through dephosphorylation [13][37][39][40]. Therefore, it is believed that a specific upstream kinase is responsible for phosphorylation and activation of ERK1/2 [41]. Subsequently, this kinase was found to be a dual-specificity kinase that phosphorylates threonine and tyrosine on ERK and is activated by nerve growth factor or epidermal growth factor, named MAP kinase kinase (MKK) or MAPK/ERK kinase (MEK) [42][43]. The kinase were cloned by independent groups [44][45]. Like ERK, MEK is also under negative regulation by dephosphorylation [13]. Further studies of the kinase cascade have revealed that Raf is an upstream kinase that controls MEK activity by phosphorylation. Thus, Raf kinase was positioned as the first serine/threonine upstream kinase of the canonical MEK-ERK pathway in 1992 [3] and a direct effector of Ras in 1993 [4][46][47].

3. Role of Raf in Biology

Genetic knockouts of different Raf isoforms in mice all lead to embryonic lethality or severe growth retardation and abnormal development [48][49][50]. Thus, A-Raf knockout mice were born alive but showed severe intestinal distension and neurological defects and died around postnatal day 20 [48]. B-Raf knockout mice succumbed in utero at embryonic day 12.5 due to massive bleeding in the body cavity, with severe vascular and neuronal abnormalities [49]. The phenotypes are attributed to increased apoptosis of endothelial cells and endothelial precursor cells in embryos and large blood vessels [51]. Ablation of C-Raf is fatal from embryonic day 10.5 to day 12.5, with dysplasia of the placenta, liver, hematopoietic organs, profound deafness and increased apoptosis of tissue cells [50][52][53][54]. It has been shown that C-Raf plays a critical role in the regulation of cell proliferation and suppression of apoptosis during embryogenesis [54]. A-Raf acts as a B-Raf effector and participates in Ras signaling when C-Raf is exhausted [55]. Moreover, A-Raf stabilizes B-Raf–C-Raf interaction to maintain signaling efficiency, especially in the presence of Raf inhibitors [55]. However, the cellular function of individual Raf is still less clear. Complex connections and interactions exist among them, which may depend on cell types or developmental stages.
Raf kinase family kinases play important roles in oncogenesis, inasmuch as they act as key effectors downstream of Ras, whose mutations account for oncogenesis in approximately 30% of human cancers, and as mediator for other oncogenes [11][55][56][57]. B-Raf has attracted great interest since the report that it was found to be mutated in 66% of malignant melanomas in 2002 [58]. Over 100 mutations in B-Raf have been identified in cancer patients. Most B-Raf mutations are concentrated in two regions: the glycine-rich P loop of the N lobe, and the activation segment and flanking regions in the kinase domain [59]. Among them, the most common mutation is a single amino acid substitution of valine 600 (V600, some reports designated V599) for glutamic acid, accounting for up to 90% of the mutations [58][60][61]. While most of the mutations significantly increase the kinase activity, some (e.g., B-Raf G595R) exhibit impaired activity and cannot phosphorylate MEK directly [62]. However, the B-Raf mutants with decreased kinase activity could hyper-stimulate the ERK pathway [59][63]. Therefore, the oncogenic mechanism of B-Raf is fundamentally different from that of the constitutively activated v-Raf found in murine retrovirus [64].
Although mutations of Raf-1 are much rarer in cancer than B-Raf, several studies have reported germline mutations of C-Raf in human diseases. For example, two mutations, S427G and I448V, are found in the kinase domain of C-Raf in patients with therapy-related acute myeloid leukemia [65]. The mutation of S427G causes increased activity of the Raf/MEK/ERK pathway, while I448V mutation does not affect the kinase activity. This research suggests that these germline mutations of C-Raf are predisposing factors for human neoplasia. In addition, mutation of C-Raf has been documented in “RASopathies”—a diverse collection of disorders caused by germline mutations in genes that code for the components or regulators of the RAS-RAF-MEK-ERK pathway. The disorders are characterized by postnatal short stature and neurocognitive delay, including neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, cardio-facio-cutaneous syndrome and Legius syndrome [66][67][68].
In terms of dimerization state, there are three major types of B-Raf mutations described in human cancers (Figure 1). The most common one is the Class I with V600E mutation, which renders the kinase active as a monomer. The mutation mimics phosphorylation of the activation loop, leading to disruption of inactive conformation [58]. Class II mutations, including K601E, L597Q, and G469A, cause spontaneous dimerization, resulting in the activation of the kinase. These mutations destabilize auto-inhibition by disrupting the inhibitory interaction of the activation loop with the Gly-rich loop and disable feedback suppression of Raf dimers [69]. Class III mutations impair kinase activity toward MEK and adopt a tumor-specific mechanism by which the mutants transactivate endogenous C-Raf through phosphorylation of the activation loop by forming B-Raf–C-Raf heterodimers [70]. Unlike Class I and Class II mutants, Class III mutants bind to Ras more tightly than wild-type B-Raf. Intriguingly, mutations equivalent to B-Raf V600E in C-Raf and A-Raf fail to produce oncogenic effects unless a negative charge is introduced into the NtA-region. These results support the notion that the regulation of C-Raf and A-Raf kinase domains is tighter because mutations at the two sites are required to confer transforming ability [69][71].
Figure 1. Functional classes of B-Raf mutations. Class I B-Raf mutants contain V600E/D mutations in the activation loop which can signal as active monomers, independent of Ras. Class II B-Raf mutants are Ras-independent and signal as dimers. Class III B-Raf mutants have reduced kinase activity and drive the activation of ERK signaling by transactivating wild-type Raf which signals as mutant B-Raf–wild-type C-Raf dimers. These mutants require active Ras to trigger a signaling cascade.

References

  1. Lavoie, H.; Therrien, M. Regulation of RAF protein kinases in ERK signalling. Nat. Rev. Mol. Cell. Biol. 2015, 16, 281–298.
  2. Matallanas, D.; Birtwistle, M.; Romano, D.; Zebisch, A.; Rauch, J.; von Kriegsheim, A.; Kolch, W. Raf family kinases: Old dogs have learned new tricks. Genes Cancer 2011, 2, 232–260.
  3. Kyriakis, J.M.; App, H.; Zhang, X.F.; Banerjee, P.; Brautigan, D.L.; Rapp, U.R.; Avruch, J. Raf-1 activates MAP kinase-kinase. Nature 1992, 358, 417–421.
  4. Zhang, X.F.; Settleman, J.; Kyriakis, J.M.; Takeuchi-Suzuki, E.; Elledge, S.J.; Marshall, M.S.; Bruder, J.T.; Rapp, U.R.; Avruch, J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 1993, 364, 308–313.
  5. Rapp, U.R.; Goldsborough, M.D.; Mark, G.E.; Bonner, T.I.; Groffen, J.; Reynolds, F.H., Jr.; Stephenson, J.R. Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc. Natl. Acad. Sci. USA 1983, 80, 4218–4222.
  6. Brown, K.; Quintanilla, M.; Ramsden, M.; Kerr, I.B.; Young, S.; Balmain, A. v-ras genes from Harvey and BALB murine sarcoma viruses can act as initiators of two-stage mouse skin carcinogenesis. Cell 1986, 46, 447–456.
  7. Shimizu, K.; Goldfarb, M.; Suard, Y.; Perucho, M.; Li, Y.; Kamata, T.; Feramisco, J.; Stavnezer, E.; Fogh, J.; Wigler, M.H. Three human transforming genes are related to the viral ras oncogenes. Proc. Natl. Acad. Sci. USA 1983, 80, 2112–2116.
  8. Ladeda, V.; Frankel, P.; Feig, L.A.; Foster, D.A.; Bal de Kier Joffe, E.; Aguirre-Ghiso, J.A. RalA mediates v-Src, v-Ras, and v-Raf regulation of CD44 and fibronectin expression in NIH3T3 fibroblasts. Biochem. Biophys. Res. Commun. 2001, 283, 854–861.
  9. Pisapia, P.; Pepe, F.; Iaccarino, A.; Sgariglia, R.; Nacchio, M.; Russo, G.; Gragnano, G.; Malapelle, U.; Troncone, G. BRAF: A Two-Faced Janus. Cells 2020, 9, 2549.
  10. Leevers, S.J.; Marshall, C.J. Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. EMBO J. 1992, 11, 569–574.
  11. Cox, A.D.; Der, C.J. Ras history: The saga continues. Small GTPases 2010, 1, 2–27.
  12. Malumbres, M.; Barbacid, M. RAS oncogenes: The first 30 years. Nat. Rev. Cancer 2003, 3, 459–465.
  13. Ahn, N.G. The MAP kinase cascade. Discovery of a new signal transduction pathway. Mol. Cell. Biochem. 1993, 127–128, 201–209.
  14. Akbani, R.; Akdemir, K.C.; Aksoy, B.A.; Albert, M.; Ally, A.; Amin, S.B.; Kwong, L.N. Genomic Classification of Cutaneous Melanoma. Cell 2015, 161, 1681–1696.
  15. Karoulia, Z.; Gavathiotis, E.; Poulikakos, P.I. New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 2017, 17, 676–691.
  16. Hancock, J.F. Ras proteins: Different signals from different locations. Nat. Rev. Mol. Cell. Biol. 2003, 4, 373–384.
  17. Garnett, M.J.; Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 2004, 6, 313–319.
  18. Kimura, E.T.; Nikiforova, M.N.; Zhu, Z.; Knauf, J.A.; Nikiforov, Y.E.; Fagin, J.A. High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003, 63, 1454–1457.
  19. Rajagopalan, H.; Bardelli, A.; Lengauer, C.; Kinzler, K.W.; Vogelstein, B.; Velculescu, V.E. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002, 418, 934.
  20. Never-smoker, N.E.S. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014, 511, 543–550.
  21. Tiacci, E.; Trifonov, V.; Schiavoni, G.; Holmes, A.; Kern, W.; Martelli, M.P.; Pucciarini, A.; Bigerna, B.; Pacini, R.; Wells, V.A.; et al. BRAF mutations in hairy-cell leukemia. N. Engl. J. Med. 2011, 364, 2305–2315.
  22. Rapp, U.R.; Reynolds, F.H., Jr.; Stephenson, J.R. New mammalian transforming retrovirus: Demonstration of a polyprotein gene product. J. Virol. 1983, 45, 914–924.
  23. Rapp, U.R.; Cleveland, J.L.; Fredrickson, T.N.; Holmes, K.L.; Morse, H.C., 3rd; Jansen, H.W.; Patschinsky, T.; Bister, K. Rapid induction of hemopoietic neoplasms in newborn mice by a raf(mil)/myc recombinant murine retrovirus. J. Virol. 1985, 55, 23–33.
  24. Jansen, H.W.; Lurz, R.; Bister, K.; Bonner, T.I.; Mark, G.E.; Rapp, U.R. Homologous cell-derived oncogenes in avian carcinoma virus MH2 and murine sarcoma virus 3611. Nature 1984, 307, 281–284.
  25. Rapp, U.R.; Todaro, C. Generation of new mouse sarcoma viruses in cell culture. Science 1978, 201, 821–824.
  26. Moelling, K.; Heimann, B.; Beimling, P.; Rapp, U.R.; Sander, T. Serine- and threonine-specific protein kinase activities of purified gag-mil and gag-raf proteins. Nature 1984, 312, 558–561.
  27. Bonner, T.I.; Kerby, S.B.; Sutrave, P.; Gunnell, M.A.; Mark, G.; Rapp, U.R. Structure and biological activity of human homologs of the raf/mil oncogene. Mol. Cell. Biol. 1985, 5, 1400–1407.
  28. Bonner, T.; O’Brien, S.J.; Nash, W.G.; Rapp, U.R.; Morton, C.C.; Leder, P. The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4. Science 1984, 223, 71–74.
  29. Ikawa, S.; Fukui, M.; Ueyama, Y.; Tamaoki, N.; Yamamoto, T.; Toyoshima, K. B-raf, a new member of the raf family, is activated by DNA rearrangement. Mol. Cell. Biol. 1988, 8, 2651–2654.
  30. Huleihel, M.; Goldsborough, M.; Cleveland, J.; Gunnell, M.; Bonner, T.; Rapp, U.R. Characterization of murine A-raf, a new oncogene related to the v-raf oncogene. Mol. Cell. Biol. 1986, 6, 2655–2662.
  31. Han, M.; Golden, A.; Han, Y.; Sternberg, P.W.C. C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature 1993, 363, 133–140.
  32. Ambrosio, L.; Mahowald, A.P.; Perrimon, N. Requirement of the Drosophila raf homologue for torso function. Nature 1989, 342, 288–291.
  33. Barnier, J.V.; Papin, C.; Eychène, A.; Lecoq, O.; Calothy, G. The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression. J. Biol. Chem. 1995, 270, 23381–23389.
  34. Storm, S.M.; Cleveland, J.L.; Rapp, U.R. Expression of raf family proto-oncogenes in normal mouse tissues. Oncogene 1990, 5, 345–351.
  35. Sturgill, T.W.; Ray, L.B.; Erikson, E.; Maller, J.L. Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 1988, 334, 715–718.
  36. Courchesne, W.E.; Kunisawa, R.; Thorner, J. A putative protein kinase overcomes pheromone-induced arrest of cell cycling in S. cerevisiae. Cell 1989, 58, 1107–1119.
  37. Ray, L.B.; Sturgill, T.W. Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo. Proc. Natl. Acad. Sci. USA 1988, 85, 3753–3757.
  38. Lindberg, R.A.; Quinn, A.M.; Hunter, T. Dual-specificity protein kinases: Will any hydroxyl do? Trends Biochem. Sci. 1992, 17, 114–119.
  39. Anderson, N.G.; Maller, J.L.; Tonks, N.K.; Sturgill, T.W. Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase. Nature 1990, 343, 651–653.
  40. Ullah, R.; Yin, Q.; Snell, A.H.; Wan, L. RAF-MEK-ERK pathway in cancer evolution and treatment. Semin. Cancer Biol. 2021.
  41. Dent, P.; Haser, W.; Haystead, T.A.; Vincent, L.A.; Roberts, T.M.; Sturgill, T.W. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science 1992, 257, 1404–1407.
  42. Gómez, N.; Cohen, P. Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases. Nature 1991, 353, 170–173.
  43. Ahn, N.G.; Seger, R.; Bratlien, R.L.; Diltz, C.D.; Tonks, N.K.; Krebs, E.G. Multiple components in an epidermal growth factor-stimulated protein kinase cascade. In vitro activation of a myelin basic protein/microtubule-associated protein 2 kinase. J. Biol. Chem. 1991, 266, 4220–4227.
  44. Crews, C.M.; Alessandrini, A.; Erikson, R.L. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 1992, 258, 478–480.
  45. Zheng, C.F.; Guan, K.L. Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J. Biol. Chem. 1993, 268, 11435–11439.
  46. Vojtek, A.B.; Hollenberg, S.M.; Cooper, J.A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 1993, 74, 205–214.
  47. Warne, P.H.; Viciana, P.R.; Downward, J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 1993, 364, 352–355.
  48. Pritchard, C.A.; Bolin, L.; Slattery, R.; Murray, R.; McMahon, M. Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. Curr. Biol. 1996, 6, 614–617.
  49. Wojnowski, L.; Zimmer, A.M.; Beck, T.W.; Hahn, H.; Bernal, R.; Rapp, U.R.; Zimmer, A. Endothelial apoptosis in Braf-deficient mice. Nat. Genet. 1997, 16, 293–297.
  50. Wojnowski, L.; Stancato, L.F.; Zimmer, A.M.; Hahn, H.; Beck, T.W.; Larner, A.C.; Rapp, U.R.; Zimmer, A. Craf-1 protein kinase is essential for mouse development. Mech. Dev. 1998, 76, 141–149.
  51. Wiese, S.; Pei, G.; Karch, C.; Troppmair, J.; Holtmann, B.; Rapp, U.R.; Sendtner, M. Specific function of B-Raf in mediating survival of embryonic motoneurons and sensory neurons. Nat. Neurosci. 2001, 4, 137–142.
  52. De Iriarte Rodríguez, R.; Magariños, M.; Pfeiffer, V.; Rapp, U.R.; Varela-Nieto, I. C-Raf deficiency leads to hearing loss and increased noise susceptibility. Cell Mol. Life Sci. 2015, 72, 3983–3998.
  53. Hüser, M.; Luckett, J.; Chiloeches, A.; Mercer, K.; Iwobi, M.; Giblett, S.; Sun, X.M.; Brown, J.; Marais, R.; Pritchard, C. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 2001, 20, 1940–1951.
  54. Mikula, M.; Schreiber, M.; Husak, Z.; Kucerova, L.; Rüth, J.; Wieser, R.; Zatloukal, K.; Beug, H.; Wagner, E.F.; Baccarini, M. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J. 2001, 20, 1952–1962.
  55. Rebocho, A.P.; Marais, R. ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. Oncogene 2013, 32, 3207–3212.
  56. Dumaz, N.; Hayward, R.; Martin, J.; Ogilvie, L.; Hedley, D.; Curtin, J.A.; Bastian, B.C.; Springer, C.; Marais, R. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006, 66, 9483–9491.
  57. McPhillips, F.; Mullen, P.; MacLeod, K.G.; Sewell, J.M.; Monia, B.P.; Cameron, D.A.; Smyth, J.F.; Langdon, S.P. Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis 2006, 27, 729–739.
  58. Davies, H.; Bignell, G.R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M.J.; Bottomley, W.; et al. Mutations of the BRAF gene in human cancer. Nature 2002, 417, 949–954.
  59. Wan, P.T.; Garnett, M.J.; Roe, S.M.; Lee, S.; Niculescu-Duvaz, D.; Good, V.M.; Jones, C.M.; Marshall, C.J.; Springer, C.J.; Barford, D.; et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004, 116, 855–867.
  60. Wellbrock, C.; Karasarides, M.; Marais, R. The RAF proteins take centre stage. Nat. Rev. Mol. Cell. Biol. 2004, 5, 875–885.
  61. Kumar, R.; Angelini, S.; Czene, K.; Sauroja, I.; Hahka-Kemppinen, M.; Pyrhönen, S.; Hemminki, K. BRAF mutations in metastatic melanoma: A possible association with clinical outcome. Clin. Cancer Res. 2003, 9, 3362–3368.
  62. Dhomen, N.; Marais, R. New insight into BRAF mutations in cancer. Curr. Opin. Genet. Dev. 2007, 17, 31–39.
  63. Garnett, M.J.; Rana, S.; Paterson, H.; Barford, D.; Marais, R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell 2005, 20, 963–969.
  64. Tran, N.H.; Frost, J.A. Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition. J. Biol. Chem. 2003, 278, 11221–11226.
  65. Zebisch, A.; Staber, P.B.; Delavar, A.; Bodner, C.; Hiden, K.; Fischereder, K.; Janakiraman, M.; Linkesch, W.; Auner, H.W.; Emberger, W.; et al. Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia. Cancer Res. 2006, 66, 3401–3408.
  66. Pandit, B.; Sarkozy, A.; Pennacchio, L.A.; Carta, C.; Oishi, K.; Martinelli, S.; Pogna, E.A.; Schackwitz, W.; Ustaszewska, A.; Landstrom, A.; et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 2007, 39, 1007–1012.
  67. Razzaque, M.A.; Nishizawa, T.; Komoike, Y.; Yagi, H.; Furutani, M.; Amo, R.; Kamisago, M.; Momma, K.; Katayama, H.; Nakagawa, M.; et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat. Genet. 2007, 39, 1013–1017.
  68. Rauen, K.A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 2013, 14, 355–369.
  69. Yao, Z.; Torres, N.M.; Tao, A.; Gao, Y.; Luo, L.; Li, Q.; de Stanchina, E.; Abdel-Wahab, O.; Solit, D.B.; Poulikakos, P.I.; et al. BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell 2015, 28, 370–383.
  70. Yao, Z.; Yaeger, R.; Rodrik-Outmezguine, V.S.; Tao, A.; Torres, N.M.; Chang, M.T.; Drosten, M.; Zhao, H.; Cecchi, F.; Hembrough, T.; et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 2017, 548, 234–238.
  71. Yaeger, R.; Corcoran, R.B. Targeting Alterations in the RAF-MEK Pathway. Cancer Discov. 2019, 9, 329–341.
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