The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting

Wykosky, Jill; Debinski, Waldemar

doi:10.1158/1541-7786.mcr-08-0244

Cited by 268 publications

(298 citation statements)

References 131 publications

(176 reference statements)

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“…54 Worthy of further studies is the hepatic expression level of EPHRIN-A1 and its receptor during dietinduced NAFLD, because of the many cellular functions that these proteins pursue in physiological and pathological conditions. 55,56 The real role of p38MAPK upregulation in the NAFLD pathogenesis is still unclear even though it was previously demonstrated that this kinase together with ERK is remarkably activated in rodent models of NAFLD. 57 Our data, agree with other studies which found that hepatic expression of FLT1 mRNA was decreased in obese mice compared with lean mice and suggest a potential involvement of vascular endothelial growth factor and its receptor in the pathogenesis of NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Alisi

Sacco

Bruscalupi

et al. 2011

Laboratory Investigation

178

116

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Nonalcoholic fatty liver disease (NAFLD) is an emerging disease with a broad spectrum of liver conditions. The complex molecular pathogenesis of NAFLD is still unclear. In this study, we conducted an analysis of microRNA (miRNA) expression profiles in liver of rats made NAFLD by different diets. To this aim, Sprague-Dawley rats were fed ad libitum for 3 months with different diets: standard diet (SD), diet enriched in fats and low in carbohydrates (HFD), SD with high fructose (SD-HF) and diet with high levels of fats and fructose (HFD-HF). Our results demonstrated that the treatment with different dietetic regimens caused a significant increase of the body weight and the alteration of some metabolic parameters compared with control animals, as well as various liver injuries. The miRNAs analysis showed the significant downregulation of three miRNAs (miR-122, miR-451 and miR-27) and the upregulation of miR-200a, miR-200b and miR-429 in HFD, SD-HF and HFD-HF rats. Besides, miR-21 expression was significantly decreased only in fructose-enriched diets. These miRNAs target molecules involved in the control of lipid and carbohydrate metabolism, signal transduction, cytokine and chemokine-mediated signaling pathway and apoptosis. Western blot analysis of PKCd, LITAF, ALDOLASE-A, p38MAPK, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 showed a diet-induced deregulation of all these proteins. Interestingly, the expression pattern of LITAF, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 might be well explained by the trend of their specific mRNAs, by potentially regulatory miRNAs, or both. In conclusion, we highlight for the first time the potential involvement of novel determinants (miRNAs and proteins) in the molecular pathogenesis of diet-induced NAFLD.

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Section: Discussionmentioning

confidence: 99%

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Alisi

Sacco

Bruscalupi

et al. 2011

Laboratory Investigation

178

116

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“…The Eph receptors are tyrosine kinases and are also divided into two classes, depending on the ephrins with which they interact. EphA2 signaling is important in development and shows functional alterations in cancer 85 . Ephrin-A1, the natural ligand for EphA2, is a GPI-linked protein, and the two interact in a juxtacrine configuration.…”

Section: Epha2 Receptor Tyrosine Kinase Triggering By Ephrin-a1mentioning

confidence: 99%

Molecular mechanisms in signal transduction at the membrane

Groves

Kuriyan

2010

Nat Struct Mol Biol

262

255

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Signal transduction originates at the membrane, where the clustering of signaling proteins is a key step in transmitting a message. Membranes are difficult to study, and their influence on signaling is still only understood at the most rudimentary level. Recent advances in the biophysics of membranes, surveyed in this review, have highlighted a variety of phenomena that are likely to influence signaling activity, such as local composition heterogeneities and long-range mechanical effects. We discuss recent mechanistic insights into three signaling systems-Ras activation, Ephrin signaling and the control of actin nucleation-where the active role of membrane components is now appreciated and for which experimentation on the membrane is required for further understanding.The influence of the membrane surface environment on the behavior of proteins that are localized to the vicinity of the membrane is still poorly understood. This contrasts starkly with our now quite sophisticated understanding of the structural and chemical aspects of the individual protein components 1 . This lack of knowledge is a natural consequence of the fact that membranes are difficult to study in vitro and that detailed quantitative information is difficult to obtain in vivo 2 . The relative inaccessibility of membranes to classical methods of study effectively cloaks their role in signaling biochemistry. We suggest that what is known about membranes in signal transduction is just a glimmer of a much larger story, with many key aspects of membrane function still hidden beneath the cloak.Cell signaling relies on modular domains that generate protein-protein interactions at the membrane 3,4 . Equally critical are domains that recognize specific phospholipids and are thereby responsive to changes in membrane composition 5 , as best exemplified by the family of protein kinase C (PKC) isozymes 6,7 . The PKC isozymes transduce signals arising from the hydrolysis of phospholipids in the membrane and have a protein kinase domain linked to C1 domains and a C2 domain (Fig. 1). The C1 domains bind to diacylglycerol (DAG), whereas the C2 domain binds to negatively charged lipids, such as phosphatidylinositol-4,5,-bisphosphate (PIP 2 ) and to Ca 2+ ions 6,7 . The activation of PKC involves priming by phosphorylation, followed by the recruitment of PKC to the membrane by PIP 2 , Ca 2+ and DAG 7,8 . One important principle that emerged from PKC studies is that the individual lipidbinding modules of PKC have insufficient affinity for their target lipids and so require that both PIP 2 and DAG be present for effective activation of the enzyme. This requirement for © 2010 Nature America, Inc. All rights reserved. Correspondence should be addressed to J.K. (kuriyan@berkeley.edu) or J.T.G. (Jtgroves@lbl.gov). COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Published as: Nat Struct Mol Biol. 2010 June ; 17(6): 659-665. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptmultiple targeting signals is ofte...

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“…The Eph receptor tyrosine kinases and ephrin ligands have been studied extensively for their roles in developmental processes. However, in recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression (Wykosky and Debinski, 2008). Eph2A, as well as other members of the Eph receptor tyrosine kinase family, have been associated with advanced ovarian cancer and poor clinical outcome (Thaker et al, 2004;Wu et al, 2006;Kumar et al, 2007;Alam et al, 2008).…”

mentioning

confidence: 99%

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Glas

Dering

et al. 2009

Br J Cancer

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BACKGROUND: Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer. METHODS: We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs. RESULTS: Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC 50 values (IC 50 range: 0.001 -11.3 mmol l À1 ). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73 -1.11) or paclitaxel (mean CI values, range: 0.76 -1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib. CONCLUSIONS: These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

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The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting

Cited by 268 publications

References 131 publications

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Molecular mechanisms in signal transduction at the membrane

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

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