2015
DOI: 10.1158/1541-7786.mcr-15-0165
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Abstract: K-Ras4B is a highly oncogenic Ras isoform and is the only isoform associated with initiation of adenocarcinomas. Mechanistic insight into why and how K-Ras4B mediates ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. The current review points out the overlooked but critical role of calmodulin (CaM) which selectively binds to GTP-bound K-Ras4B; but not to its isoforms. Cell proliferation and growth require the MAPK (Ras/Raf/MEK/ERK) and PI3K/Akt signaling pathways. … Show more

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Cited by 75 publications
(100 citation statements)
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References 131 publications
(140 reference statements)
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“…It also regulates the RASSF (Ras association domain family) [20], which can link Ras activation and Hippo pathway signalling. The three major Ras pathways include Raf/MEK (MAPK kinase)/ERK (extracellular-signal-regulated kinase) pathway [21,22], PI3K/Akt/mTOR (mammalian target of rapamycin) pathway [23][24][25], and RalGDS/RalGEF (Raslike guanine-nucleotide-exchange factor)/Ral pathway [26,27]. Among them, only the Raf/MEK/ERK pathway is regulated through Ras dimerization [5,6]; other Ras signalling pathways are activated by monomeric Ras [28].…”
Section: Introductionmentioning
confidence: 99%
“…It also regulates the RASSF (Ras association domain family) [20], which can link Ras activation and Hippo pathway signalling. The three major Ras pathways include Raf/MEK (MAPK kinase)/ERK (extracellular-signal-regulated kinase) pathway [21,22], PI3K/Akt/mTOR (mammalian target of rapamycin) pathway [23][24][25], and RalGDS/RalGEF (Raslike guanine-nucleotide-exchange factor)/Ral pathway [26,27]. Among them, only the Raf/MEK/ERK pathway is regulated through Ras dimerization [5,6]; other Ras signalling pathways are activated by monomeric Ras [28].…”
Section: Introductionmentioning
confidence: 99%
“…Calcium modulator protein CaM binds specifically to K-Ras4B predominantly by virtue of the HVR. 94 To test the hypothesis that the conformational state of the HVR depends on Ras’ nucleotide-bound state (GDP or GTP), NMR and isothermal titration calorimetry (ITC) experiments were performed with full-length K-Ras4B–GDP/–GTP-γ-S and CaM. The results showed that no significant binding was observed between K-Ras4B–GDP and CaM, whereas K-Ras4B–GTP-γ-S can interact with CaM with micromolar affinity.…”
Section: Nucleotides and Oncogenic Mutations Affect The Conformatiomentioning
confidence: 99%
“…Activating KRAS mutations are among the earliest oncogenic genomic alterations found in pancreatic intraepithelial neoplasia (PanIN) precursor lesions and seem to be a prerequisite for the development of a fully invasive metastatic pancreatic cancer phenotype [13,14,25]. At the same time PDAC cells appear to maintain dependence on oncogenic Ras signaling for survival and proliferation [26,27,28]. Therefore, pharmacologically inhibiting oncogenic KRAS signaling has been suggested for a long time and is still considered as the Holy Grail in the quest for targeted therapeutic approaches directed against pancreatic cancer by many authors [29].…”
Section: Novel Therapeutic Targetsmentioning
confidence: 99%