Targeting cysteine rich C1 domain of Scaffold protein Kinase Suppressor of Ras (KSR) with anthocyanidins and flavonoids – a binding affinity characterization study

Dhananjayan, Karthik; Majumder, Pulak; Senthilnathan, Palanisamy; Khairunnisa, Kalathil; Venugopal, Varsha

doi:10.6026/97320630010580

Cited by 5 publications

(12 citation statements)

References 25 publications

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“…In comparison, two KSR proteins are present (KSR1 and KSR2) in C. elegans as well as mammals and have both unique and overlapping functions [26]. In all cases, KSR proteins contribute positively to ERK phosphorylation and activation [1–3]. …”

Section: Phenotypic Analysis Of Ksr Genetic Inactivationmentioning

confidence: 99%

“…KSR1 has been extensively implicated in Ras-driven cancers [6,11,14,20,23–25,28,35,37–39]. Consistent with its role as a molecular scaffold for the Raf/MEK/ERK cascade, KSR1 interacts with each kinase in this cascade [13,14,40], and increasing levels of KSR1 enhance Ras signaling to a maximum point [14].…”

Section: The Role Of Ksr In Cancermentioning

confidence: 99%

“…Substantial evidence has demonstrated that KSR proteins act as molecular scaffolds for the Raf/MEK/ERK kinase cascade [5–19]. KSR promotes Raf phosphorylation of MEK [8,44,46] and is required for maximal Ras-mediated ERK phosphorylation and activation by MEK [3,6,13,14,20,46].…”

Section: Ksr Proteins Are Molecular Scaffolds Of the Raf/mek/erk Kmentioning

confidence: 99%

“…Kinase Suppressor of Ras (KSR) proteins were identified more than 20 years ago in Drosophila (KSR) and Caenorhabditis elegans (KSR1 and KSR2) and shown to modulate Ras-mediated signaling [1–3]. It was immediately recognized that KSR had a more dominant regulatory effect on signaling from mutated Ras than wild type Ras.…”

Section: Introductionmentioning

confidence: 99%

“…In Drosophila, heterozygous mutations in KSR revert the phenotype of constitutively active Ras, Ras G12V , which speaks to the ability of KSR to regulate mutated Ras signaling [3]. Several groups have shown that KSR acts downstream of Ras as a molecular scaffold for the Raf/MEK/ERK kinase cascade [5–19]. KSR plays a role in regulating several cellular mechanisms to promote cell proliferation and survival including participation in metabolic regulation, cell cycle reinitiation following DNA damage repair, and translational regulation of key mediators of a transformed phenotype such as Myc [15,20–25].…”

Section: Introductionmentioning

confidence: 99%

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KSR as a therapeutic target for Ras-dependent cancers

Neilsen

Frodyma

Lewis

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction Targeting downstream effectors required for oncogenic Ras signaling is a potential alternative or complement to the development of more direct approaches targeting Ras in the treatment of Ras-dependent cancers. Areas covered Here we review literature pertaining to the molecular scaffold Kinase Suppressor of Ras (KSR) and its role in promoting signals critical to tumor maintenance. We summarize the phenotypes in knockout models, describe the role of KSR in cancer, and outline the structure and function of the KSR1 and KSR2 proteins. We then focus on the most recent literature that describes the crystal structure of the kinase domain of KSR2 in complex with MEK1, KSR-RAF dimerization particularly in response to RAF inhibition, and novel attempts to target KSR proteins directly. Expert opinion KSR is a downstream effector of Ras-mediated tumorigenesis that is dispensable for normal growth and development, making it a desirable target for the development of novel therapeutics with a high therapeutic index. Recent advances have revealed that KSR can be functionally inhibited using a small molecule that stabilizes KSR in an inactive conformation. The efficacy and potential for this novel approach to be used clinically in the treatment of Ras-driven cancers is still being investigated.

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Section: Phenotypic Analysis Of Ksr Genetic Inactivationmentioning

confidence: 99%

Section: The Role Of Ksr In Cancermentioning

confidence: 99%

Section: Ksr Proteins Are Molecular Scaffolds Of the Raf/mek/erk Kmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

KSR as a therapeutic target for Ras-dependent cancers

Neilsen

Frodyma

Lewis

et al. 2017

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

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Retracted: Lymphocyte‐specific protein 1 inhibits the growth of hepatocellular carcinoma by suppressing ERK1/2 phosphorylation

et al. 2016

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Lymphocyte‐specific protein 1 ( LSP 1) has been reported to regulate cell biology in several human cancers including lymphoma and breast cancer. However, the functions of LSP 1 in human hepatocellular carcinoma ( HCC ) are still unknown. In this study, we found that LSP 1 expression was downregulated in HCC tissues and cell lines, and lower LSP 1 expression was correlated with poor clinicopathological features including large tumor size, high Edmondson–Steiner grading and advanced tumor–node–metastasis ( TNM ) stage. Additionally, we demonstrated that patients with high LSP 1 expression had significantly better overall survival and disease‐free survival. Moreover, LSP 1 was found to be an independent factor for predicting the prognosis of HCC patients. In vitro and in vivo assays showed that overexpressing LSP 1 inhibited HCC growth by inducing both apoptosis and growth arrest. Mechanistically, we found that expression of phosphorylated extracellular regulated protein kinases 1 and 2 ( ERK 1/2) was downregulated after LSP 1 overexpression, indicating LSP 1 could suppress HCC growth by inhibiting the ERK pathway in HCC cells. Taken together, these results indicate that LSP 1 may serve as a prognostic marker and a potential therapeutic target in human HCC .

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An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

2015

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Most of the SOD mimics thus far developed belong to the classes of Mn-(MnPs) and Fe porphyrins(FePs), Mn(III) salens, Mn(II) cyclic polyamines and metal salts. Due to their remarkable stability we have predominantly explored Mn porphyrins, aiming initially at mimicking kinetics and thermodynamics of the catalysis of O2•− dismutation by SOD enzymes. Several MnPs are of potency similar to SOD enzymes. The in vivo bioavailability and toxicity of MnPs have been addressed also. Numerous in vitro and in vivo studies indicate their impressive therapeutic efficacy. Increasing insight into complex cellular redox biology has been accompanied by increasing awareness of complex redox chemistry of MnPs. During O2•− dismutation process, the most powerful Mn porphyrin-based SOD mimics reduce and oxidize O2•− with close to identical rate constants. MnPs reduce and oxidize other reactive species also (none of them specific to MnPs), acting as reductants (antioxidant) and pro-oxidants. Distinction must be made between the type of reactions of MnPs and the favorable therapeutic effects we observe; the latter may be of either anti- or pro-oxidative nature. H2O2/MnP mediated oxidation of protein thiols and its impact on cellular transcription seems to dominate redox biology of MnPs. It has been thus far demonstrated that the ability of MnPs to catalyze O2•− dismutation parallels all other reactivities (such as ONOO− reduction) and in turn their therapeutic efficacies. Assuming that all diseases have in common the perturbation of cellular redox environment, developing SOD mimics still seems to be the appropriate strategy for the design of potent redox-active therapeutics.

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Targeting cysteine rich C1 domain of Scaffold protein Kinase Suppressor of Ras (KSR) with anthocyanidins and flavonoids – a binding affinity characterization study

Cited by 5 publications

References 25 publications

KSR as a therapeutic target for Ras-dependent cancers

KSR as a therapeutic target for Ras-dependent cancers

Retracted: Lymphocyte‐specific protein 1 inhibits the growth of hepatocellular carcinoma by suppressing ERK1/2 phosphorylation

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

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