Signal Transduction from N-cadherin Increases Bcl-2

Tran, Nhan L.; Adams, Deanna G.; Vaillancourt, Richard; Heimark, Ronald L.

doi:10.1074/jbc.m200300200

Cited by 137 publications

(94 citation statements)

References 68 publications

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“…E-cadherin is also implicated in regulation of signal transduction through other mediators including Rho family GTPases [43], phosphatidylinositol 3-kinase (PI3K) [44,45], and epidermal growth factor (EGF) receptor [45,46], whereas N-cadherin modulates fibroblast growth factor (FGF) receptor signaling [47] as well as the PI3K/Akt pathway [48,49]. Due to the diverse nature of these dynamic multimolecular interactions, cadherins are properly positioned to functionally integrate cellcell adhesion with regulation of signal transduction pathways and their associated transcriptional programs to control multiple aspects of cell shape and behavior.…”

Section: Phenotypic Plasticity and Cadherin Expression In Eoc A Clasmentioning

confidence: 99%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

163

172

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The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

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Section: Phenotypic Plasticity and Cadherin Expression In Eoc A Clasmentioning

confidence: 99%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

163

172

View full text Add to dashboard Cite

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“…In addition to the structural role as an adhesive molecule, N-cadherin plays important roles in intracellular signaling pathways such as ␤-catenin or Wnt signaling. Also, N-cadherin-based cell-cell adhesion activates PI3K/Akt cell survival signaling by recruiting PI3K into the N-cadherin adhesion complex (12). Further, PS1 facilitates this process by promoting cadherin/PI3K association (13).…”

mentioning

confidence: 99%

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

Andō

Uemura

Kuzuya

et al. 2011

Journal of Biological Chemistry

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Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with A␤ 42 decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherinbased synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by A␤ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.Alzheimer disease (AD) 2 is pathologically characterized by the presence of amyloid ␤-peptide (A␤) and neurofibrillary tangles in the neocortex and hippocampus. Insoluble A␤ fibrillar aggregates found in senile plaques have long been considered to cause the neurodegeneration of AD. On the other hand, synaptic loss is another pathological hallmark of AD, which strongly correlates with the severity of cognitive impairment better than senile plaques or neurofibrillary tangles (1). Interestingly, recent studies from AD mouse models have shown that learning impairment and synaptic dysfunction become apparent before the formation of plaques, suggesting the hypothesis that soluble A␤ causes "synaptic failure" before plaques develop and neuron death occurs (2). Converging lines of evidence suggest that natural soluble A␤ oligomers trigger synaptic loss (3). Thus, in addition to the investigation of molecular mechanisms, which develop senile plaques and neurofibrillary tangles, research focusing on synaptic dysfunction is important to clarify the earliest pathology in AD.Presenilin (PS) 1/2 is the essential catalytic component of ␥-secretase proteolytic complex (4, 5), which is responsible for the final cleavage of amyloid precursor protein to generate A␤ peptides. Mutations in PS1 have been known as the most common cause of autosomal dominant familial Alzheimer disease (6 -8). Interestingly, PS1 binds to N-cadherin, which is an essential molecule for synaptic contact and is abundantly localized in hippocampal synapses ...

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“…In addition to cell adhesion, cadherins affect cellular functions, such as proliferation, migration, and invasion, through activation of intracellular signaling pathways, including the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway, modulation of matrix metalloproteinase functions, and association with growth factor receptors, including the fibroblast growth factor receptor (FGFR) (10,11). Aberrant cadherin expression in malignant cells is associated with epithelial-tomesenchymal transformation, cellular dedifferentiation, and invasive growth (12)(13)(14).…”

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confidence: 99%

Coexpression of two mesenchymal cadherins, cadherin 11 and N‐cadherin, on murine fibroblast‐like synoviocytes

Agarwal

Lee

Kiener

et al. 2008

Arthritis & Rheumatism

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Objective. Cadherin 11 has recently been identified on fibroblast-like synoviocytes (FLS), and studies in mice have demonstrated its importance in synovial lining architecture and inflammation. However, many tissues express more than 1 cadherin. Given the newly appreciated functional significance of cadherins in the synovium, this study was undertaken to determine whether mouse FLS express other cadherins in addition to cadherin 11.Methods. The characterization of cadherin expression was determined in FLS derived from wild-type and cadherin 11-null mice using immunofluorescence (IF), biochemical, and immunohistologic techniques.Results. Cadherin 11 expression was observed at points of cell-cell contact in cultured wild-type mouse FLS. However, despite the lack of cell surface cadherin 11, cadherin 11-null mouse FLS cells still formed intimate cell-cell contacts that contained ␤-catenin. Immunoprecipitation of cell surface biotinylated FLS with anti-␤-catenin antibody demonstrated the presence of 2 cell surface catenin-associated proteins in FLS from wild-type mice and 1 in FLS sample from cadherin 11-null mice. Using biochemical approaches and reverse transcriptase-polymerase chain reaction, these proteins were determined to be N-cadherin and cadherin 11. Expression of both N-cadherin and cadherin 11 in the synovial lining was demonstrated by immunohistochemical analysis of mouse synovium. IF analyses demonstrated colocalization of N-cadherin and cadherin 11 to the same points of cell-cell contact. However, the inability to coimmunoprecipitate both cadherins using either anti-N-cadherin or anti-cadherin 11 antibodies suggests that these cadherins are not contained within the same molecular complexes.Conclusion. These findings demonstrate that FLS express both N-cadherin and cadherin 11, and suggest that these cadherins are not contained within the same molecular complex. Given their importance in modulating cellular behavior, understanding how these cadherins regulate FLS behavior individually and in concert will be critical to understanding synovial architecture and inflammation.

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Signal Transduction from N-cadherin Increases Bcl-2

Cited by 137 publications

References 68 publications

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein

Coexpression of two mesenchymal cadherins, cadherin 11 and N‐cadherin, on murine fibroblast‐like synoviocytes

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