Functional proteomics to dissect tyrosine kinase signalling pathways in cancer

Kölch, Walter; Pitt, Andrew R.

doi:10.1038/nrc2900

Cited by 188 publications

(138 citation statements)

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“…Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57).…”

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confidence: 99%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

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confidence: 99%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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“…Dysregulation of the EGFR signaling pathway through overexpression or hyperactivation is associated with tumor development (23,25,26). A meta-analysis demonstrated that the rate of EGFR overexpression in ESCC is high and EGFR expression levels are a potential predictor of the T stage (tumor-node-metastasis classification system) (27), vascular invasion and overall survival (27).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol mediates cell cycle arrest and cell death in human esophageal squamous cell carcinoma by directly targeting the EGFR signaling pathway

Jin

Feng

et al. 2016

Oncology Letters

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Abstract.Resveratrol is a small polyphenol that has been intensively studied in a wide spectrum of therapeutic fields. More recently, resveratrol has been demonstrated to exert its antitumor activity in numerous tumor models. The present study reported that resveratrol exhibited a marked anti-proliferative effect on human esophageal squamous cell carcinoma (ESCC) cells by inducing cell cycle G 0 /G 1 phase arrest and cell death, which was associated with a decrease in the expression levels of cyclin D1 and an increase in cleaved PARP/cleaved caspase-3 expression levels. The mechanisms underlying the antitumor potency of resveratrol were principally attributed to the downregulation of epidermal growth factor receptor (EGFR) signaling. The western blotting results showed that exposure of ESCC cells to resveratrol inhibited EGF-induced EGFR activation in addition to decreasing the total protein levels of EGFR and membrane/nuclear localization. In summary, the results suggested that resveratrol, or an associated analog, may have a role in the management of human ESCC. IntroductionHuman esophageal squamous cell carcinoma (ESCC) is the 6th leading cause of cancer-associated mortality, and the 8th most common type of cancer worldwide (1). ESCC is the most common histology of esophageal cancers, and has a high incidence in China, South Africa, France and Italy (2). Epidemiological and etiological studies have previously demonstrated that certain environmental and genetic factors have crucial roles in esophageal carcinogenesis (3-7). Although there have been advances in the fields of surgery and chemotherapy, the prognosis for ESCC is typically poor as the majority of patients diagnosed are elderly and present with advanced-stage disease, rendering them unsuitable for curative resection and maintaining the five-year survival rate for ESCC at <15% (1). Therefore, improving the current understanding of the molecular mechanisms underlying ESCC pathogenesis and identifying effective therapeutic agents are required to facilitate the development of novel therapies for this disease.Resveratrol is present in red grapes, wine, nuts and common garden plants, and is one of the most intensively investigated of all the phytochemicals with putative beneficial effects on human health (8). The effects of resveratrol include anti-oxidant and anti-aging properties, improvement of insulin sensitivity and reduction of cardiovascular disease risk (9-11). Previous studies have also indicated that resveratrol is able to function as a chemo preventive and chemotherapeutic agent in certain types of human carcinomas, including those of the colorectum, skin, liver, lung, pancreas, breast and prostate (8,(12)(13)(14). Previous studies suggesting that a dietary pattern rich in resveratrol may reduce the risk of ESCC (15). However, the molecular mechanisms underlying resveratrol-induced antitumor effects have yet to be elucidated. A number of potential mechanisms have been suggested to be involved in resveratrol-induced cancer preventative effects, i...

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“…24 This signaling cascade has an amplification effect and is tightly controlled by numerous negative and positive regulators, and mis-activation of Erk can lead to numerous defects including cancer. 25 Recently it has been found that miRNAs are involved in the control of Erk activation in cardiac fibroblasts where miR-21 negatively regulates expression of the FGF signaling inhibitor, Sprouty. (a-D') Dicer -/-embryos express normal levels of Nodal, the Nodal co-activator Cripto and the Nodal convertases Spc1, 15 and Spc4.…”

confidence: 99%

MiRNA-mediated regulation of cell signaling and homeostasis in the early mouse embryo

Pernaute¹,

Spruce²,

Rodríguez³

et al. 2011

Cell Cycle

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Functional proteomics to dissect tyrosine kinase signalling pathways in cancer

Cited by 188 publications

References 148 publications

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Resveratrol mediates cell cycle arrest and cell death in human esophageal squamous cell carcinoma by directly targeting the EGFR signaling pathway

MiRNA-mediated regulation of cell signaling and homeostasis in the early mouse embryo

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