New structural and functional insight into the regulation of Ras

Kano, Yoshihito; Cook, Jonathan D.; Lee, Jeffrey E.; Ohh, Michael

doi:10.1016/j.semcdb.2016.06.006

Cited by 29 publications

(38 citation statements)

References 83 publications

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“…On the other hand, the phosphatase SHP2 has been identified by the same group to dephosphorylate pY32, thus implicating SHP2 as a direct activator of RAS activity [162]. Therefore, the latest model for the RAS activation cycle is as follows [163]. RAS activation requires SOS-induces GTP loading to RAS, along with SHP2 dephosphorylation of Y32 activate RAS.…”

Section: Signal Transductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

Wee

Wang

2017

Cancers

1,392

699

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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors.

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Section: Signal Transductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

Wee

Wang

2017

Cancers

1,392

699

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“…Our short summary and the papers of this special issue [25,29,30,33,36,39,42,52,57] highlight the promises and challenges of using signaling networks (including RAS-related signaling events) in the description of cancer initiation and development, metastasis and the emergence of drug resistance. As key messages we emphasize that…”

Section: Discussionmentioning

confidence: 99%

“…The approaches outlined above and in the contributions of this special issue [25,29,30,33,36,39,42,52,57] may overcome the current Nietzschean dilemma of cancer cell targeting: “what does not kill me makes me stronger” [60]. …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in these cases activation of wild type RAS may drive cancer upon the loss of negative RAS regulators, such as NF1, GAP or SPRY proteins [24–26]. Michael Ohh and co-workers [27] describe the structural and functional aspects of RAS regulation by non-receptor tyrosine kinases and phosphatases focusing on the structural details of SRC- and SHP2-mediated changes and related anti-cancer therapeutic options [28,29]. …”

Section: Ras As a Contextual Hub Of Signaling Network In Various mentioning

confidence: 99%

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Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

Csermely

Korcsmáros

Nussinov

2016

Seminars in Cell & Developmental Biology

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Cancer initiation and development are increasingly perceived as systems-level phenomena, where intra- and inter-cellular signaling networks of the ecosystem of cancer and stromal cells offer efficient methodologies for outcome prediction and intervention design. Within this framework, RAS emerges as a ‘contextual signaling hub’, i.e. the final result of RAS activation or inhibition is determined by the signaling network context. Current therapies often ‘train’ cancer cells shifting them to a novel attractor, which has increased metastatic potential and drug resistance. The few therapy-surviving cancer cells are surrounded by massive cell death triggering a primordial adaptive and reparative general wound healing response. Overall, dynamic analysis of patient- and disease-stage specific intracellular and intercellular signaling networks may open new areas of anticancer therapy using multitarget drugs, drugs combinations, edgetic drugs, as well as help design ‘gentler’, differentiation and maintenance therapies.

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“…Cabozantinib as a small molecule receptor tyrosine kinase inhibitor, primarily targets ret protooncogene (RET)-encoded receptor tyrosine kinase (RTK), mesenchymal epithelial transition factor (MET), and the vascular endothelial cell growth factor receptor 2 (VEGFR2), of which VEGFR2 is more sensitive. Approximately 60 RTK proteins act as high-affinity cell surface receptors for many polypeptide growth factors, cytokines, hormones, and as key regulators of physiological and pathophysiological cellular processes, through the transmembrane and/or non-transmembrane domains (Kano et al 2016;Li and Hristova 2010). One of the most important factors to influence CBT profiles of cabozantinib is the specificity and affinity of RTK binding types and efficacies in various conditions.…”

mentioning

confidence: 99%

CBT profiles of cabozantinib approved for advanced renal cell carcinomas

Wang¹

2016

Cell Biol Toxicol

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New structural and functional insight into the regulation of Ras

Cited by 29 publications

References 83 publications

Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

CBT profiles of cabozantinib approved for advanced renal cell carcinomas

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