IndraLab
Statements
sparser
"Such Ras-binding partners were identified when it was shown that galectin-1 and
galectin-3, xref respectively, act as
specific binding partners only of farnesylated active H-Ras and K-Ras. xref , xref , xref Hydrophobic binding pockets in these
galectins are the putative farnesyl-binding sites. xref , xref Galectin-1 drives the
formation and participates as an integral component of H-Ras-GTP nanoclusters, the
sites at which Raf is activated. xref Galectin-3 drives K-Ras-GTP nanoclustering, leading to robust Ras
signaling. xref Interaction of
nucleolin with N-Ras and the epidermal growth factor receptor was recently shown to
synergistically support N-Ras transformation in vitro . xref Taken together, and assuming that compounds
that block farnesyl-binding sites would act as Ras inhibitors, these findings point
to the farnesyl-binding pockets as excellent potential targets for Ras-directed
therapy."
sparser
"Then, farnesylated KRas-4B is ready for further processing: hydrolysis, catalyzed by the endopeptidase enzyme called Ras-converting enzyme 1 (RCE1); during the process, the VIM motif (HVR tail is composed of three amino acids: valine-isoleucine-methionine) of the C-terminal Cys-185 is lost in step 2."
sparser
"Although insect cells contain homologs of the two subunits of farnesyltransferase (FNTA and FNTB), it is possible that either of these proteins may not be in high enough abundance to farnesylate all of the KRAS protein, or that the insect versions of these proteins had low activity on the human KRAS4b protein."
sparser
"However, FTIs are effective at inhibiting the growth of mutant KRAS-harbouring tumours in nude mice xref and transgenic mouse models xref , suggesting that the inhibition of KRAS farnesylation is not required for FTI antitumour activity, and that, in these models, tumours are addicted to farnesylated proteins other than KRAS."
sparser
"Since the K-Ras4B/PDEδ complex which formed in bulk solution is unstable in the presence of heterogeneous membranes, delivery of PDEδ-solubilized K-Ras4B to the plasma membrane appears to be followed by the dissociation of the complex upon plasma membrane contact, and membrane binding of the released farnesylated K-Ras4B."
sparser
"Interestingly, RASSF2 is known to function as a tumor suppressor inhibiting growth of lung cancer cells via its association with farnesylated K-RAS. xref , xref In addition, in 293T embryonic kidney cells, expression of RASSF2 resulted in growth inhibition enhanced by activated K-Ras. xref Our findings in ECs are distinct from the reported effects of RASSF2 in tumor cells and in 293T embryonic kidney cells."
sparser
"The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed."
sparser
"We thus next studied K-Ras farnesylation as a function of SNORD50A and SNORD50B. There are no antibodies that specifically recognize farnesylation of K-Ras; however, PLA can detect protein post-translational modifications (PTMs) by combining an antibody to a target protein with a PTM-specific antibody, thereby only showing signal when the PTM is present on the protein of interest xref ."
sparser
"We report here that atorvastatin decreased mutant p53 expression in PO3 cells and further reduced cell growth, and we have previously reported that K-Ras undergoes farnesylation xref , thus the growth inhibition may be derived from reduced K-Ras farnesylation induced by atorvastatin."
sparser
"Similarly, in a study in which K-Ras farnesylation could be investigated independent of any confounding geranylgeranylation, comparable deprenylation of K-Ras and NDJ2 (both of which are normally farnesylated) required a 10-fold higher concentration of the FTI tipifarnib to block K-Ras [ xref ]."
sparser
"Several dozen proteins are farnesylated under basal conditions and tipifarnib treatment blocks their prenylation ( xref ), but inhibition of the farnesylation of KRAS and NRAS leads to compensatory geranylgeranylation and the restoration of membrane localization in the presence of tipifarnib ( xref , xref )."
sparser
"This includes an effective delivery of PDEδ-solubilized K-Ras4B to the plasma membrane, probably through cytoplasmic diffusion, the dissociation of the K-Ras4B/PDEδ complex upon plasma membrane contact, and finally the membrane binding of released farnesylated K-Ras4B that leads to K-Ras4B-enriched microdomain formation."
sparser
"Unfortunately, the previous studies certificated that the clinical trials of Kras inhibitors, aimed at Kras C-terminal farnesylation, did not show any significantly statistical difference [ xref , xref ] and the clinical trials of inhibitors against downstream signaling proteins RAF and MEK were also not successful [ xref – xref ]."
sparser
"Salirasib, a farnesylcystein mimetic interfering with the binding of farnesylated K-Ras4B to the Ras-escort protein Galectin, has at best shown modest clinical efficacy in early phase trials both as a single-agent and in combination with conventional chemotherapy [ xref , xref ]."
sparser
"The three Ras isoforms, HRAS, KRAS and NRAS have a conserved guanine nucleotide-binding domain (G domain) but use different C-terminal anchors for membrane binding: HRAS and NRAS undergoand acylation, whereas KRAS is only farnesylated and requires an adjacent polybasic domain for stable anchoring xref ."
sparser
"However, in a recent study, Chung et al. [ xref ] showed that full-length farnesylated and methylated K-Ras4B remains monomeric by itself over a wide range of surface densities in multiple types of membrane compositions using fluorescence correlation spectroscopy and single-molecule tracking."
sparser
"It should also be noted that other proteins are involved in Ras signaling regulation, such as UBIAD1, which interacts with the C-terminal region of HRas and modulates its trafficking from the Golgi apparatus to the plasma membrane [ xref ] or the prenyl-binding protein PDEδ, regulating the correct localization and signaling by farnesylated KRas [ xref ]."
sparser
"To further investigate the influence of the membrane on the conformational dynamics of the HVR, we simulated the farnesylated K-Ras4B on the surface of an anionic lipid bilayer consisting of DOPC:DOPS (mole ratio 4:1). xref Based on the NMR CSP data of K-Ras4B binding to nanodiscs, xref four different initial configurations of each GDP- and GTP-bound WT K-Ras4B with the farnesylation on Cys185 were placed on the membrane surface to represent the diversity of K-Ras4B–membrane interactions."
sparser
"In the presence of FTase inhibitors, the decreased biological activity of farnesylated K-Ras is compensated for by another form of K-Ras post-translational modification: geranylgeranylation by GGTase I. Therefore, many research centers and institutes have focused on the identification of ICMT inhibitors."
sparser
"However, there are currently no available treatment options for KRAS -mutant lung adenocarcinomas compared with tumours with mutations in other oncogenes, xref as strategies targeting KRAS farnesylation, MEK activation and BRAF have either failed or yielded no responses. xref – xref "
sparser
"One basis for this failure was predicted years earlier when it was found unexpectedly that, when FTase activity is blocked by FTI treatment, K-Ras4B and N-Ras proteins are no longer farnesylated but instead become substrates for the related prenyltransferase geranylgeranyltransferase-I (GGTase I) that catalyses addition of a C20 geranylgeranyl isoprenoid group xref – xref ."
sparser
"Essential studies by Hancock and colleagues have established that farnesylated K-Ras is mainly localized in non-raft microdomains through the electrostatic interaction of its PBD with the plasma membrane and it is recruited into nanoclusters after GTP loading [ xref , xref , xref ]."
sparser
"Farnesylation of the nonmethylated K-Ras 4B peptide enhances its affinity to vesicles containing acidic phospholipids (phosphatidylglycerol or phosphatidylserine) by 70-fold, and methylation leads to an additional dramatic (150-fold) increase in membrane affinity.(ABSTRACT TRUNCATED AT 250 WORDS)"
sparser
"Independent studies from our laboratory have shown that loss of CAV1 also has striking effects on nanoscale organization of the plasma membrane, including increased clustering of phosphatidylserine and farnesylated K-ras but decreased nanoclustering of dually palmitoylated H-ras xref ."