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_6 label "Selventa" provenance.
_5 value "Raf may also be activated by Ras-independent elements and, in turn, propagates signals through diverse effectors that mediate proliferation, angiogenesis, metastases, and survival.5 Raf may be activated by signaling upstream or constitutively. Constitutive activation of Raf and Ras are indistinguishable in their potential to induce malignant transformation.6-8 Activating raf mutations have been identified in melanoma, thyroid, colon, and other cancers (Table 1).9-43 Furthermore, the disappointing clinical results of farnesyltransferase (FTase) inhibitors (FTIs) that were developed based on a flawed premise that they would effectively target malignancies with a high incidence of Ras mutation has led to scrutiny of signaling elements downstream of Ras, such as Raf, as therapeutic targets.44 This review highlights relevant information about the biology of Raf and novel strategies directed at exploiting this knowledge to more effectively treat malignant diseases. SIGNALING THROUGH THE MAPK PATHWAY The molecular mechanisms and signaling pathways that regulate cell proliferation and survival are receiving considerable attention as potential targets for anticancer strategies. 45,46 Recently, there has been a notable increase in efforts directed at targeting the MAPK pathway, which integrates a wide array of proliferative signals initiated by receptor tyrosine kinases (RTKs) and G protein- coupled receptors.47,48 The network of signals emanating from the MAPK pathway are transmitted by proteins that serve as chemical switches, cycling between phosphorylated (activated) and dephosphorylated (inactivated) states.49 These on and off switches are regulated by kinases and phosphatases, respectively. Activated signaling elements, in turn, phosphorylate amino acid residues on downstream signaling proteins in a cascade-like and expansive manner.50 Not only does the centrality of the MAPK pathway render its components important targets for therapeutic development, but many genes that encode for its critical signaling elements undergo mutations, constitutively activating downstream signaling elements and conferring the potential for transformation and autonomous growth.50-52 In addition to efforts directed at Ras, therapeutic strategies directed at the MAPK pathway are targeting the cascade of downstream effector proteins including Raf, MAPK kinase (MAPKK; also called MEK or extracellular signal-regulated kinase [ERK] kinase), and ERK. The Raf/MEK/ERK module (Fig 1) of the MAPK pathway, which is immediately downstream of Ras, may be less redundant and innately resistant to therapeutic manipulations compared with Ras (as discussed in the next section). The Unfilled Promise of Targeting Ras The Raf/MEK/ERK module of the MAPK pathway has been the focus of considerable attention because therapeutic efforts directed at Ras, which is situated at the apex of the MAPK pathway, have been disappointing.44 Ras belongs to a superfamily of guanine nucleotide triphosphatases (GTPases) that transmit proliferative and survival signals to the MAPK, phosphatidylinositol 3-kinase (PI3K), and other pathways (Figs 1 and 2). Three ras proto-oncogenes encode four 21-kd proteins, called p21ras or Ras (H-Ras, N-Ras, K-Ras4A, and K-Ras4B, resulting from two alternatively spliced K-Ras gene products), that are localized to the inner surface of the cell membrane.44 Of the three ras genes, K-ras mutations are most commonly found in solid malignancies, whereas N-ras mutations are encountered less often, and H-ras mutations are rarely encountered.53,54 Ras isoforms impart distinct biologic effects as a result of the potential of these proteins to differentially activitate critical effectors.55 After synthesis as inactive cytosolic propeptides, Ras undergoes a series of post-translational modifications at its carboxyl terminus that increase its hydrophobicity.56,57 These modifications render Ras functional and capable of lo..." provenance.
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assertion hadPrimarySource 16170185 provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
assertion wasDerivedFrom _5 provenance.
large_corpus.bel authoredBy _6 provenance.
large_corpus.bel version "1.4" provenance.