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_7 label "Selventa" provenance.
_6 value "It is in the cell membrane where Ras cycles between inactive guanosine diphosphate-bound and active guanosine triphosphate (GTP) -bound states, thereby activating a series of effector kinases that phosphorylate a cascade of signaling proteins.58 Ras mutants exhibit slightly less intrinsic GTPase activity than wild-type Ras; however, the principal consequence of the mutated proteins is a marked decrease in interactions between Ras and its GTPase activator protein.59 Instead of reverting to its inactive guanosine diphosphate-bound state, the modified conformation of mutant Ras favors its active GTP-bound state, which has a higher propensity to activate downstream effectors even in the absence of growth factor stimulation, conferring a proliferative advantage to tumors. The considerable attention paid to targeting Ras as a therapeutic strategy is based on the high incidence of activating ras mutations in human malignancies, including approximately 22% of non-small-cell lung, 50% of colorectal, and 90% of pancreatic cancers.53,60,61 Of the strategies directed at Ras, targeting FTase has received the most attention, but the FTIs are not Ras specific, and a bonafide Ras-specific therapeutic agent has not yet been evaluated in clinical trials.62,63 Fortunately, because K-ras mutations constitute most ras mutations in the aforementioned malignancies, in which the therapeutic expectations of FTIs were among the highest, the failure of this strategy should not be surprising because geranylgeranyl transferase I can alternatively prenylate K-ras, rendering it functional even when FTase is completely inhibited. 64,65 Although the FTIs have shown notable antitumor activity in patients with advanced breast cancer and some hematologic malignancies, the low ras mutation rates in these cancers suggest that farnesylation of other critical proteins is being inhibited.66 DOWNSTREAM OF RAS: RAF AND OTHER RAS EFFECTORS Localization of GTP-bound Ras to the inner surface of the cell membrane activates several downstream effectors, most notably the serine/threonine kinase Raf, which is the first signaling element in the MAPK pathway.2,67,68 As shown in Figure 1, other downstream effectors of Ras include the PI3K cell survival pathway, the small GTP-binding proteins Rac and Rho, and the stress-activated protein kinase pathway (also referred to as the c-jun N-terminal kinase [JNK] pathway).69-71 In addition, in response to cellular stress and cytokine stimulation mediated through Ras, the dual-specificity p38MAPK kinases (MKK3 and MKK6) and the JNK kinases (MKK4 and MKK7) phosphorylate p38MAPK and JNK, respectively.72-76 GTP-bound Ras interacts directly with Raf and mobilizes the inactive protein from the cytoplasm (Figs 1 and 2). Once the Ras-Raf complex is translocated to the cell membrane, Ras activates the serine/threonine kinase function of Raf through an association between its Ras-binding domain (RBD) in the amino-terminal regulatory region and Ras-GTP. This is followed by a series of Ras-dependent phosphorylation events and conformational changes, which will be described later in this review.77-84 The regulatory mechanisms of various Raf isoforms differ in that A-Raf and C-Raf require additional phosphorylation reactions for activity, whereas B-Raf has a much higher level of basal kinase activity.85 Raf is also activated by Ras-independent activators, including the soluble non-RTK Src and Janus kinase 1," provenance.
_6 wasQuotedFrom 16170185 provenance.
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 _6 provenance.
large_corpus.bel authoredBy _7 provenance.
large_corpus.bel version "1.4" provenance.