KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors

McCall, Jamie L.; Gehring, Drew; Clymer, Beth K.; Fisher, Kurt W.; Das, B.; Kelly, David L.; Kim, Hyun‐Seok; White, Michael A.; Lewis, Robert E.

doi:10.1128/mcb.00087-16

Cited by 32 publications

(44 citation statements)

References 84 publications

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“…A gene expression high-throughput screen termed Functional Signature Ontology (FUSION) was developed to detect effectors of KSR1-dependent signaling in Ras-driven tumors and identify small molecules that can target those effectors 68 . Recent results from FUSION detected hits that mediate KSR1-dependent signals and promote the viability of human colon tumor cells but have no similar role on non-transformed human colon epithelial cells 69 , 70 . These observations suggest the existence of multiple effectors that may be used to support the survival in tumor cells in a manner distinct from their role in normal tissue.…”

Section: Ksr Proteins As Targets For Therapymentioning

confidence: 99%

Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

Frodyma¹,

Neilsen²,

Costanzo-Garvey³

et al. 2017

F1000Res

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Many cancers, including those of the colon, lung, and pancreas, depend upon the signaling pathways induced by mutated and constitutively active Ras. The molecular scaffolds Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) play potent roles in promoting Ras-mediated signaling through the Raf/MEK/ERK kinase cascade. Here we summarize the canonical role of KSR in cells, including its central role as a scaffold protein for the Raf/MEK/ERK kinase cascade, its regulation of various cellular pathways mediated through different binding partners, and the phenotypic consequences of KSR1 or KSR2 genetic inactivation. Mammalian KSR proteins have a demonstrated role in cellular and organismal energy balance with implications for cancer and obesity. Targeting KSR1 in cancer using small molecule inhibitors has potential for therapy with reduced toxicity to the patient. RNAi and small molecule screens using KSR1 as a reference standard have the potential to expose and target vulnerabilities in cancer. Interestingly, although KSR1 and KSR2 are similar in structure, KSR2 has a distinct physiological role in regulating energy balance. Although KSR proteins have been studied for two decades, additional analysis is required to elucidate both the regulation of these molecular scaffolds and their potent effect on the spatial and temporal control of ERK activation in health and disease.

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Section: Ksr Proteins As Targets For Therapymentioning

confidence: 99%

Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

Frodyma¹,

Neilsen²,

Costanzo-Garvey³

et al. 2017

F1000Res

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show abstract

“…The current study expands upon previous work that used FUSION to identify microRNAs and individual genes as potential therapeutic targets in cancer 6 , 7 , 27 . This study demonstrates the ability of FUSION to identify novel small molecules from an unbiased screen of crude natural product fractions that inhibit a specific target important for cancer cell survival.…”

Section: Discussionmentioning

confidence: 56%

“…Fu nctional Si gnature On tology (FUSION) detects functional relationships between genes and microRNAs based on changes to a gene expression-based functional signature 6 , 7 , 27 . Previously, FUSION identified AMPKγ1 as a genetic functional analog of KSR1 based on unsupervised hierarchical clustering and quantification of similarity metrics (Euclidean distance and Pearson correlation) based on reporter gene expression following RNAi-mediated depletion of individual genes from a genome-scale human siRNA library.…”

Section: Resultsmentioning

confidence: 99%

A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells

Das

Neilsen

Fisher

et al. 2018

Sci Rep

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AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. We used Functional Signature Ontology (FUSION) to screen a natural product library to identify compounds that were inhibitors of AMPK to test its potential for detecting small molecules with preferential toxicity toward human colon tumor cells. FUSION identified 5′-hydroxy-staurosporine, which competitively inhibits AMPK. Human colon cancer cell lines are notably more sensitive to 5′-hydroxy-staurosporine than are non-transformed human colon epithelial cells. This study serves as proof-of-concept for unbiased FUSION-based detection of small molecule inhibitors of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development.

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“…An additional KSR-regulated mechanism promoting the expression of PGC1β has recently been described where KSR1 promotes ERK activation in colon cancer cells, which is required for increased MYC translation. MYC then acts as a transcription factor and increases PGC1β transcript levels [24]. KSR proteins also plays a role as an overall metabolic regulator in cells by regulating glucose metabolism [22] and adipogenesis [15].…”

Section: Non-canonical Functions Of Ksr Proteinsmentioning

confidence: 99%

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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KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors

Cited by 32 publications

References 84 publications

Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells

KSR as a therapeutic target for Ras-dependent cancers

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