Soluble E-cadherin promotes cell survival by activating epidermal growth factor receptor

Inge, Landon J.; Barwe, Sonali P.; D'Ambrosio, Julia A.; Gopal, Jegan; Lu, Kan V.; Ryazantsev, Sergey; Rajasekaran, Sigrid A.; Rajasekaran, Ayyappan K.

doi:10.1016/j.yexcr.2010.12.025

Cited by 47 publications

(60 citation statements)

References 39 publications

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“…Previous reports from our laboratory have demonstrated that sEcad retains the ability to interact with E-cadherin, and that E-cadherin is necessary for the anti-apoptotic effect of sE-cad in MDCK cells (Inge et al, 2011). E-cadherin homophilic adhesion between adjacent cells transiently activates the EGFR and its downstream PI3K-AKT and ERK1/2 signaling cascades, thereby inducing cell survival and differentiation (Pece and Gutkind, 2000).…”

Section: -Test) (Ef) Representative Immunoblots From Two Independenmentioning

confidence: 95%

“…Activation of the EGFR has been implicated in sE-cad-mediated proliferation, migration and invasion effects (Brouxhon et al, 2007(Brouxhon et al, , 2013aInge et al, 2011;Maretzky et al, 2005;Najy et al, 2008;Noe et al, 2001). We therefore hypothesized that the induction of lumen filling by MSV-MDCK cell co-culture is mediated by the activation of EGFR signaling in MDCK cysts.…”

Section: Msv-mdck Cells Mediate Lumen Filling Through Activation Of Egfrmentioning

confidence: 99%

“…Purification of sE-cad sE-cad was purified from the sE-cad-overexpressing HEK-293T cells using Ni-NTA resin as described previously (Inge et al, 2011). Briefly, sE-cadoverexpressing HEK-293T cells were generated by stably expressing the pSEC-Tag2-SECAD vector into HEK-293T cells and stable clones were selected with Zeocin (Invitrogen).…”

Section: D Matrigel™ Culturesmentioning

confidence: 99%

“…In human skin, breast, prostate and ovarian cancer cells, the pathophysiological consequences of sE-cad activity include enhanced tumor cell migration and invasion, induction of proinvasive MMPs and increased cell signaling, all of which ultimately promote tumor progression (Brouxhon et al, 2007(Brouxhon et al, , 2014a(Brouxhon et al, , 2013bDavid and Rajasekaran, 2012;Noe et al, 2001;Symowicz et al, 2007;Zuo et al, 2011). We have previously demonstrated that sEcad acts as a survival factor and prevents apoptosis in normal epithelial cells (Inge et al, 2011). However, it is not known whether the sE-cad present in the TME impacts normal tissue architecture.…”

Section: Introductionmentioning

confidence: 99%

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Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

Patil

D'Ambrosio

Inge

et al. 2015

Journal of Cell Science

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In epithelial cancers, carcinoma cells coexist with normal cells. Although it is known that the tumor microenvironment (TME) plays a pivotal role in cancer progression, it is not completely understood how the tumor influences adjacent normal epithelial cells. In this study, a three-dimensional co-culture system comprising non-transformed epithelial cells (MDCK) and transformed carcinoma cells (MSV-MDCK) was used to demonstrate that carcinoma cells sequentially induce preneoplastic lumen filling and epithelial-mesenchymal transition (EMT) in epithelial cysts. MMP-9 secreted by carcinoma cells cleaves cellular E-cadherin (encoded by CDH1) from epithelial cells to generate soluble E-cadherin (sE-cad), a pro-oncogenic protein. We show that sE-cad induces EGFR activation, resulting in lumen filling in MDCK cysts. Long-term sE-cad treatment induced EMT. sE-cad caused lumen filling by induction of the ERK signaling pathway and triggered EMT through the sustained activation of the AKT pathway. Although it is known that sE-cad induces MMP-9 release and consequent EGFR activation in tumor cells, our results, for the first time, demonstrate that carcinoma cells can induce sE-cad shedding in adjacent epithelial cells, which leads to EGFR activation and the eventual transdifferentiation of the normal epithelial cells.

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Section: -Test) (Ef) Representative Immunoblots From Two Independenmentioning

confidence: 95%

Section: Msv-mdck Cells Mediate Lumen Filling Through Activation Of Egfrmentioning

confidence: 99%

Section: D Matrigel™ Culturesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

Patil

D'Ambrosio

Inge

et al. 2015

Journal of Cell Science

Self Cite

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“…Alternatively, the extracellular domain of E-cadherin could play a role in preventing activation of EGFR, because shedding of E-cadherin has been implicated in EGF-dependent activation of the PI3K/AKT and MAPK pathways and subsequent cell survival (47). Thus, although further research is needed to delineate the exact mechanism that controls the sensitization of GFR signaling upon p120 loss, we propose that increased sensitization of GFR signaling may be caused by a relieve of direct or indirect mechanical restriction, or inhibition of ligand binding as a result of steric hindrance between the adherens junction and GFRs.…”

Section: P120 Loss Sensitizes Cells To Gfr Signalingmentioning

confidence: 99%

Loss of p120-Catenin Induces Metastatic Progression of Breast Cancer by Inducing Anoikis Resistance and Augmenting Growth Factor Receptor Signaling

et al. 2013

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Metastatic breast cancer remains the chief cause of cancer-related death among women in the Western world. Although loss of cell-cell adhesion is key to breast cancer progression, little is known about the underlying mechanisms that drive tumor invasion and metastasis. Here, we show that somatic loss of p120-catenin (p120) in a conditional mouse model of noninvasive mammary carcinoma results in formation of stromal-dense tumors that resemble human metaplastic breast cancer and metastasize to lungs and lymph nodes. Loss of p120 in anchorage-dependent breast cancer cell lines strongly promoted anoikis resistance through hypersensitization of growth factor receptor (GFR) signaling. Interestingly, p120 deletion also induced secretion of inflammatory cytokines, a feature that likely underlies the formation of the prometastatic microenvironment in p120-negative mammary carcinomas. Our results establish a preclinical platform to develop tailored intervention regimens that target GFR signals to treat p120-negative metastatic breast cancers. Cancer Res; 73(15); 4937-49. Ó2013 AACR.

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Beyond a tumor suppressor: Soluble E‐cadherin promotes the progression of cancer

Kuang

Yang³

et al. 2016

Intl Journal of Cancer

105

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E-cadherin (E-cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane-tethered form and a soluble form. Full-length E-cad is membrane tethered. As a type I transmembrane glycoprotein, E-cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E-cad (sE-cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full-length E-cad. The production of sE-cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE-cad can diffuse into the extracellular environment and the blood. As a paracrine/ autocrine signaling molecule, sE-cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE-cad in tumorigenesis and tumor progression and its significance in clinical therapeutics.

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Soluble E-cadherin promotes cell survival by activating epidermal growth factor receptor

Cited by 47 publications

References 39 publications

Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

Loss of p120-Catenin Induces Metastatic Progression of Breast Cancer by Inducing Anoikis Resistance and Augmenting Growth Factor Receptor Signaling

Beyond a tumor suppressor: Soluble E‐cadherin promotes the progression of cancer

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