PTPRK negatively regulates transcriptional activity of wild type and mutated oncogenic β-catenin and affects membrane distribution of β-catenin/E-cadherin complexes in cancer cells

Novellino, Luisa; Filippo, Annamaria De; Deho, Paola; Perrone, Francesco; Pilotti, Silvana; Parmiani, Giorgio; Castelli, Chiara

doi:10.1016/j.cellsig.2007.12.024

Cited by 43 publications

(55 citation statements)

References 26 publications

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“…4E). Overall, these results indicate that LOX-PP increases the level of the P subunit of RPTP-, which has been shown to relocalize ␤-catenin to the cell membrane, and decreases the levels of the RPTP-PIC subunit, which facilitates ␤-catenin movement to the nucleus (2,34).…”

Section: Vol 31 2011 Lox-pp Rptp-interaction Inhibits ␤-Catenin Actmentioning

confidence: 82%

“…RPTP-is a member of the receptor-like protein tyrosine phosphatase family that is involved in the regulation of cell contact formation (9). We focused on RPTP-due to the accumulating evidence of its role as a tumor suppressor gene that is often silenced or deleted in human tumors (34). The RPTP gene maps to a putative tumor suppressor gene region in chromosome 6 and is a potential deletion target in a variety of tumors, including pancreatic cancer, breast cancer, ovarian carcinoma, melanoma, leukemia, non-Hodgkin lymphoma, and primary central nervous system lymphomas (7,34,48).…”

Section: Discussionmentioning

confidence: 99%

“…We focused on RPTP-due to the accumulating evidence of its role as a tumor suppressor gene that is often silenced or deleted in human tumors (34). The RPTP gene maps to a putative tumor suppressor gene region in chromosome 6 and is a potential deletion target in a variety of tumors, including pancreatic cancer, breast cancer, ovarian carcinoma, melanoma, leukemia, non-Hodgkin lymphoma, and primary central nervous system lymphomas (7,34,48). In addition, RPTP-is reported to be upregulated by TGF-␤ treatment in primary human keratinocytes and is involved in the negative regulation of signal pathways induced by receptor tyrosine kinases (34,47).…”

Section: Discussionmentioning

confidence: 99%

“…At the cellular membrane, the RPTP-P isoform associates with ␤-catenin and ␥-catenin (plakoglobin) (9), two key molecules involved in the formation of cell-cell adhesions, and mediates homophilic intercellular interactions. This association with RPTP-stabilizes E-cadherin-␤-catenin complexes at cell-tocell contact regions, decreasing the pool of ␤-catenin in the cytoplasmic and nuclear compartments (34). In contrast, the PIC isoform functions as an activator of ␤-catenin transcriptional activity by chaperoning it to the nucleus, possibly by facilitating the dephosphorylation of ␤-catenin-associated factors for TCF activation (2).…”

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confidence: 99%

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The Lysyl Oxidase Propeptide Interacts with the Receptor-Type Protein Tyrosine Phosphatase Kappa and Inhibits β-Catenin Transcriptional Activity in Lung Cancer Cells

Sánchez-Morgan

Kirsch

Trackman

et al. 2011

Molecular and Cellular Biology

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The propeptide region of the lysyl oxidase proenzyme (LOX-PP) has been shown to inhibit Ras signaling in NIH 3T3 and lung cancer cells with activated RAS, but its mechanism of action is poorly understood. Here, a yeast two-hybrid assay of LOX-PP-interacting proteins identified a clone encoding the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa (RPTP-), and the interaction of the two proteins in mammalian cells was confirmed. RPTP-is proteolytically processed to isoforms that have opposing effects on ␤-catenin activity. The RPTP-transmembrane P subunit interacts with and sequesters ␤-catenin at the cell membrane, where it can associate with E-cadherin and promote intercellular interactions. At high cell density, further processing of the P subunit yields a phosphatase intracellular portion (PIC) subunit, which chaperones ␤-catenin to the nucleus, where it can function to activate transcription. Lung cancer cells were found to contain higher PIC levels than untransformed lung epithelial cells. In H1299 lung cancer cells, ectopic LOX-PP expression reduced the nuclear levels of PIC by increasing its turnover in the lysosome, thereby decreasing the nuclear levels and transcriptional activity of ␤-catenin while increasing ␤-catenin membrane localization. Thus, LOX-PP is shown to negatively regulate pro-oncogenic ␤-catenin signaling in lung cancer cells.The enzyme lysyl oxidase (LOX) catalyzes oxidative modifications that promote the formation of lysine-derived covalent cross-links needed for the normal structural integrity of the extracellular matrix. LOX is synthesized as a 50-kDa inactive proenzyme (pro-LOX), which is N-and O-glycosylated within sites of the propeptide domain (45), secreted, and then cleaved to the functional C-terminal ϳ30-kDa enzyme and an ϳ18-kDa N-terminal lysyl oxidase propeptide (LOX-PP). Another major function of the LOX gene was discovered with the observation that its expression inhibited the transforming activity of the H-Ras oncogene in NIH 3T3 fibroblasts (6,22). Consistent with this finding, many cancers and derived cell lines display reduced levels of LOX protein or RNA (3,5,12,16,17,22,24,25,38). LOX reexpression was also seen in stable phenotypic revertants of Ras-transfected NIH 3T3 cells following interferon treatment (5, 22). These and other findings led Contente et al. (5) to term the LOX gene the Ras recision gene (rrg). Subsequently, pro-LOX was shown to inhibit the activities of the Akt and Erk kinases and NF-B transcription factors in Ras-transformed NIH 3T3 cells (19), and ectopic expression of the LOX gene in gastric cancer cells resulted in reduced tumor formation in nude mice (21). More recently, our group noted that LOX-PP was sufficient to mediate the rrg activity of the LOX gene in Ras-transformed NIH 3T3 cells (35). Consistent with these findings, Bouez et al. showed that LOX protein expression was absent from human basal and squamous cell carcinomas and that a reduction in LOX mRNA levels but not enzyme activity caused a more in...

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Section: Vol 31 2011 Lox-pp Rptp-interaction Inhibits ␤-Catenin Actmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Lysyl Oxidase Propeptide Interacts with the Receptor-Type Protein Tyrosine Phosphatase Kappa and Inhibits β-Catenin Transcriptional Activity in Lung Cancer Cells

Sánchez-Morgan

Kirsch

Trackman

et al. 2011

Molecular and Cellular Biology

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“…It is not yet clear whether the action of Hakai influences b-catenin signaling. Recently, the tyrosine phosphatases PTPRK and PCP-2 have been shown to inhibit b-catenin signaling and increase E-cadherin-dependent adhesion (Yan et al 2006;Novellino et al 2008). The cumulative evidence suggests that tyrosine phosphorylation-dependent destabilization of cadherin/ b-catenin complexes and tyrosine-phosphorylation-dependent activation of b-catenin can both activate signaling and induce EMT.…”

Section: Phosphorylation and The Control Of B-catenin In Signaling Anmentioning

confidence: 99%

Interplay of Cadherin-Mediated Cell Adhesion and Canonical Wnt Signaling

Heuberger¹,

Birchmeier²

2009

Cold Spring Harbor Perspectives in Biology

550

528

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The epithelial-mesenchymal transition is essential in both embryonic development and the progression of carcinomas. Wnt signaling and cadherin-mediated adhesion have been implicated in both processes; clarifying their role will depend on linking them to rearrangements of cellular structure and behavior. b-Catenin is an essential molecule both in cadherinmediated cell adhesion and in canonical Wnt signaling. Numerous experiments have shown that the loss of cadherin-mediated cell adhesion can promote b-catenin release and signaling; this is accomplished by proteases, protein kinases and other molecules. Cadherin loss can also signal to several other regulatory pathways. Additionally, many target genes of Wnt signaling influence cadherin adhesion. The most conspicuous of these Wnt target genes encode the transcription factors Twist and Slug, which directly inhibit the E-cadherin gene promoter. Other Wnt/b-catenin target genes encode metalloproteases or the cell adhesion molecule L1, which favor the degradation of E-cadherin. These factors provide a mechanism whereby cadherin loss and increased Wnt signaling induce epithelialmesenchymal transition in both carcinomas and development.

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Whole‐exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1

McPherson

Ong

et al. 2015

Cancer Medicine

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Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of multiple neurofibromas, cafe‐au‐lait spots, and Lisch nodules. Individuals with NF1 are at increased risk of developing various tumors, such as malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, leukemia, glioma, rhabdomyosarcoma, and breast cancer. Here, we describe the exome sequencing of breast cancer, MPNST, and neurofibroma from a patient with NF1. We identified a germline mutation in the NF1 gene which resulted in conversion of leucine to proline at amino acid position 847. In addition, we showed independent somatic NF1 mutations in all the three tumors (frameshift insertion in breast cancer (p.A985fs), missense mutation in MPNST (p.G23R), and inframe deletion in dermal neurofibroma (p.L1876del‐Inf)), indicating that a second hit in NF1 resulting in the loss of function could be important for tumor formation. Each tumor had a distinct genomic profile with mutually exclusive mutations in different genes. Copy number analysis revealed multiple copy number alterations in the breast cancer and the MPNST, but not the benign neurofibroma. Germline loss of chromosome 6q22.33, which harbors two potential tumor suppressor genes, PTPRK and LAMA2, was also identified; this may increase tumor predisposition further. In the background of NF1 syndrome, although second‐hit NF1 mutation is critical in tumorigenesis, different additional mutations are required to drive the formation of different tumors.

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PTPRK negatively regulates transcriptional activity of wild type and mutated oncogenic β-catenin and affects membrane distribution of β-catenin/E-cadherin complexes in cancer cells

Cited by 43 publications

References 26 publications

The Lysyl Oxidase Propeptide Interacts with the Receptor-Type Protein Tyrosine Phosphatase Kappa and Inhibits β-Catenin Transcriptional Activity in Lung Cancer Cells

The Lysyl Oxidase Propeptide Interacts with the Receptor-Type Protein Tyrosine Phosphatase Kappa and Inhibits β-Catenin Transcriptional Activity in Lung Cancer Cells

Interplay of Cadherin-Mediated Cell Adhesion and Canonical Wnt Signaling

Whole‐exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1

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