KSR and CNK: two scaffolds regulating RAS-mediated RAF activation

Clapéron, Audrey; Therrien, Marc

doi:10.1038/sj.onc.1210408

Cited by 122 publications

(104 citation statements)

References 116 publications

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“…This is consistent with studies pointing to the involvement of the MEK/Erk1/2 cascade in control of TF expression [21]. However, it should also be borne in mind that the kinase [14,22,23] scaffolding functions [15,24,25] and other functions of KSR1 are still poorly understood and therefore the exact nature of the linkage between this protein and TF remains to be established. Indeed, even though one of the main functions of KSR1 is thought to be the in the physical assembly of the elements of the raf/MEK/MAPK cascade downstream of ras and EGFR, it is possible that additional proteins interacting with KSR1 (e.g.…”

Section: Discussionsupporting

confidence: 88%

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Xing

Milsom

et al. 2010

Thrombosis Research

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Introduction: Tissue factor (TF) is the key trigger of the coagulation cascade and the membrane signalling receptor for coagulation protease, factor VIIa. In cancer, TF has been implicated in cancer cell survival, growth, and angiogenesis, and is upregulated as a result of oncogenic transformation. Materials and Methods:We assayed TF expression and tumourigenicity in mice of human cancer cell lines expressing oncogenic receptor tyrosine kinases. These cells were subjected to modulation of the kinase suppressor of ras 1 (KSR1) levels and treated with oncoprotein inhibitors in vitro and in vivo.Results: Here we show that herceptin, AG1478 and CI-1033 inhibitors of two different members of the ErbB family of oncogenes (HER-2 and EGFR) reduce TF levels in epithelial cancer cells. In EGFR-driven A431 cells, TF upregulation is diminished upon genetic targeting of KSR1, the scaffolding protein involved in EGFR signalling. Conversely, upregulation of KSR1 in A431 cells increases their TF expression and tumourigenicity in mice. The latter property remains dependent on EGFR, as pan-Erb (EGFR) inhibitor, CI-1033 blocks TF promoter activity and tumour formation by parental and KSR1 overexpressing A431 cells.

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Section: Discussionsupporting

confidence: 88%

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Xing

Milsom

et al. 2010

Thrombosis Research

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“…Abnormal expression of scaffold proteins has been linked to different types of cancer in human (Claperon and Therrien, 2007). Ezrin-radixinmoesin-(ERM)-binding phosphoprotein 50 (EBP50; also named NHERF-1 for Na þ /H þ exchanger regulatory factor-1) is a scaffold protein that is strongly expressed in the liver, and in particular beneath the plasma membrane of biliary epithelial cells (Fouassier et al, 2001(Fouassier et al, , 2009.…”

Section: Introductionmentioning

confidence: 99%

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

et al. 2011

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Scaffold proteins form multiprotein complexes that are central to the regulation of intracellular signaling. The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is highly expressed at the plasma membrane of normal biliary epithelial cells and binds epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with oncogenic properties. This study investigated EBP50-EGFR interplay in biliary cancer. We report that in a collection of 106 cholangiocarcinomas, EBP50 was delocalized to the cytoplasm of tumor cells in 66% of the cases. Ectopic expression of EBP50 was correlated with the presence of satellite nodules and with the expression of EGFR, which was at the plasma membrane, implying a loss of interaction with EBP50 in these cases. In vitro, loss of interaction between EBP50 and EGFR was mimicked by EBP50 depletion using a small interfering RNA approach in human biliary carcinoma cells co-expressing the two proteins at their plasma membrane, and in which interaction between EBP50 and EGFR was validated. EBP50 depletion caused an increase in EGFR expression at their surface, and a sustained activation of the receptor and of its downstream effectors (extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3) in both basal and EGF-stimulated conditions. Cells lacking EBP50 showed epithelial-to-mesenchymal transition-associated features, including reduction in E-cadherin and cytokeratin-19 expression, induction of S100A4 and of the E-cadherin transcriptional repressor, Slug, and loss of cell polarity. Accordingly, depletion of EBP50 induced the disruption of adherens junctional complexes, the development of lamellipodia structures and the subsequent acquisition of motility properties. All these phenotypic changes were prevented upon inhibition of EGFR tyrosine kinase by gefitinib. These findings indicate that loss of EBP50 at the plasma membrane in tumor cells may contribute to biliary carcinogenesis through EGFR activation.

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“…Des études sur des souris chez lesquelles le gène KSR1 fut inactivé ont confirmé son rôle dans la signalisation RAS/MAPK et ont montré que l'inactivation du gène provoque une perturbation du développement de tumeurs mammaires ou de papillomes RAS dépendants [25,26]. De plus, KSR1 et KSR2 semblent également avoir la capacité d'agir comme adaptateurs liant RAF, MEK et ERK [26,27]. Il convient de noter cependant qu'il existe très peu de données fonctionnelles sur KSR2.…”

Section: Apport Des Modèles Génétiquesunclassified

“…Il convient de noter cependant qu'il existe très peu de données fonctionnelles sur KSR2. Finalement, l'inactivité de KSR en tant que catalyseur protéine kinase demeure toutefois contestée par certains [27].…”

Section: Apport Des Modèles Génétiquesunclassified

“…Chez les mammifères, deux des trois homologues de CNK, CNK1 et CNK2, interagissent également avec RAF et jouent un rôle dans la signalisation MAPK. Toutefois, l'importance du rôle de CNK1 et CNK2 semble varier selon le RTK stimulant la voie [27]. Pour ce qui est des deux homologues de HYP chez les mammifères, SAMD10 (SAM domain containing 10) et SAMD12, aucune étude n'est actuellement disponible à leur sujet.…”

Section: Apport Des Modèles Génétiquesunclassified

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