Desmosomal plakophilin 2 as a differentiation marker in normal and malignant tissues

Mertens, Claudia; Kühn, Caecilia; Moll, Roland; Schwetlick, Ina; Franke, Werner W.

doi:10.1046/j.1432-0436.1999.6450277.x

Cited by 77 publications

(27 citation statements)

References 47 publications

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“…Therefore, it is critical to explore alternative mechanisms of inhibiting receptor activation and downstream signaling. PKP2 expression is increased in many cancers, such as breast, prostate, colorectal, pancreatic, oropharyngeal, and bladder cancers (14,(18)(19)(20)(21). Increased PKP2 expression also correlates with the elevated malignancy of many cancers.…”

Section: Discussionmentioning

confidence: 99%

“…We found that a cytoplasmic protein, PKP2, interacted with EGFR. Several clinical studies have indicated that PKP2 expression is abnormally high in various cancers and that PKP2 is a potential biomarker for cancer diagnosis (14,(18)(19)(20)(21). However, the molecular basis for PKP2 expression in cancer is unclear.…”

Section: Pkp2 Interacts With Egfrmentioning

confidence: 99%

“…Although the N-terminal head domains of PKPs are quite diversified, a consensus sequence termed the HR2 motif is shared by all the PKP head domains (12,13). PKP2 was originally isolated as a desmosomal protein, but additional studies have shown that it is also found in the cytoplasm and nucleus (14). Mutations of PKP2 are related to the cardiac disorder arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), and PKP2-deficient mice showed early-stage embryonic lethality due to abnormal heart morphogenesis, demonstrating that PKP2 is important for normal heart development and function (15)(16)(17).…”

mentioning

confidence: 99%

“…Mutations of PKP2 are related to the cardiac disorder arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), and PKP2-deficient mice showed early-stage embryonic lethality due to abnormal heart morphogenesis, demonstrating that PKP2 is important for normal heart development and function (15)(16)(17). Although the mechanisms have not yet been identified, PKP2 overexpression is also associated with cancer malignancy as determined on the basis of several clinical and immunohistochemical analyses (14,(18)(19)(20)(21).…”

mentioning

confidence: 99%

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Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Arimoto

Burkart

Yan

et al. 2014

Molecular and Cellular Biology

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Epidermal growth factor (EGF) receptor (EGFR) has been implicated in tumor development and invasion. Dimerization and autophosphorylation of EGFR are the critical events for EGFR activation. However, the regulation of EGF-dependent and EGFindependent dimerization and phosphorylation of EGFR has not been fully understood. Here, we report that cytoplasmic protein plakophilin-2 (PKP2) is a novel positive regulator of EGFR signaling. PKP2 specifically interacts with EGFR via its N-terminal head domain. Increased PKP2 expression enhances EGF-dependent and EGF-independent EGFR dimerization and phosphorylation. Moreover, PKP2 knockdown reduces EGFR phosphorylation and attenuates EGFR-mediated signal activation, resulting in a significant decrease in proliferation and migration of cancer cells and tumor development. Our results indicate that PKP2 is a novel activator of the EGFR signaling pathway and a potential new drug target for inhibiting tumor growth.

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Section: Discussionmentioning

confidence: 99%

Section: Pkp2 Interacts With Egfrmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Arimoto

Burkart

Yan

et al. 2014

Molecular and Cellular Biology

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“…PKP2 has also been implicated in promoting oncogenesis and it has been reported that PKP2 expression is higher in various cancers, especially at their metastatic stage [42–49] . However, the role of PKP2 in the development of cancer, as well as cancer progression, was unclear.…”

Section: Pkp2 a Novel Desmosomal Protein For Egfr Dimerizationmentioning

confidence: 99%

Plakophilin-2 induced EGFR phosphorylation: a focus on the intracellular activators of EGFR

Arimoto¹,

Weng²,

Zhang

2015

Receptor Clin Invest

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The oncogenic role of EGFR in many tumors has attracted a great deal of attention in the recent years and initiated the development of several potent EGFR inhibitors, which are used clinically for cancer treatment. However, the current therapeutic inhibition of EGFR signaling is limited to monoclonal antibodies that bind to the EGFR extracellular domain or tyrosine kinase inhibitors that block EGFR kinase activation directly. Despite the great promise of these inhibitors, a certain percentage of patients develop resistance to these therapies, highlighting the necessity for alternative therapeutic strategies based on our most current knowledge of the mechanisms of EGFR signaling. We recently reported that Plakofilin-2 (PKP2) is a novel ligand-independent cytoplasmic activator of EGFR signaling. Here we focus on recent studies demonstrating important roles of intracellular EGFR activators, and propose targeted disruption of these activators as a novel avenue of therapeutic intervention to inhibit EGFR-mediated cancer development.

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Upregulation of plakophilin‐2 and its acquisition to adherens junctions identifies a novel molecular ensemble of cell–cell‐attachment characteristic for transformed mesenchymal cells

Rickelt

Winter-Simanowski

Noffz

et al. 2009

Intl Journal of Cancer

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In contrast to the desmosome-containing epithelial and carcinoma cells, normal and malignantly transformed cells derived from mesenchymal tissues and tumors are connected only by adherens junctions (AJs) containing N-cadherins and/or cadherin-11, anchored in a cytoplasmic plaque assembled by a-and b-catenin, plakoglobin, proteins p120 and p0071. Here, we report that the AJs of many malignantly transformed cell lines are characterized by the additional presence of plakophilin-2 (Pkp2), a protein hitherto known only as a major component of desmosomal plaques, i.e., AJs of epithelia and carcinomatous cells. This massive acquisition of Pkp2 and its integration into AJ plaques of a large number of transformed cell lines is demonstrated with biochemical and immunolocalization techniques. Upregulation of Pkp2 and its integration into AJs has also been noted in some soft tissue tumors in situ and some highly proliferative colonies of cultured mesenchymal stem cells. As Pkp2 has recently been identified as a functionally important major regulatory organizer in AJs and related junctions in epithelial cells and cardiomyocytes, we hypothesize that the integration of Pkp2 into AJs of ''soft tissue tumor'' cells also can serve functions in the upregulation of proliferation, the promotion of malignant growth in general as well as the close-packing of diverse kinds of cells and the metastatic behavior of such tumors. We propose to examine its presence in transformed mesenchymal cells and related tumors and to use it as an additional diagnostic criterion. ' 2009 UICC

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Desmosomal plakophilin 2 as a differentiation marker in normal and malignant tissues

Cited by 77 publications

References 47 publications

Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Plakophilin-2 induced EGFR phosphorylation: a focus on the intracellular activators of EGFR

Upregulation of plakophilin‐2 and its acquisition to adherens junctions identifies a novel molecular ensemble of cell–cell‐attachment characteristic for transformed mesenchymal cells

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