The Experts below are selected from a list of 858 Experts worldwide ranked by ideXlab platform
Annette Borchers - One of the best experts on this subject based on the ideXlab platform.
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PTK7 faces the wnt in development and disease
Frontiers in Cell and Developmental Biology, 2017Co-Authors: Hanna Berger, Andreas Wodarz, Annette BorchersAbstract:PTK7 (protein tyrosine kinase 7) is an evolutionarily conserved transmembrane receptor regulating various processes in embryonic development and tissue homeostasis. On a cellular level PTK7 affects the establishment of cell polarity, the regulation of cell movement and migration as well as cell invasion. The PTK7 receptor has been shown to interact with ligands, co-receptors and intracellular transducers of Wnt signaling pathways, pointing to a function in the fine-tuning of the Wnt signaling network. Here we will review recent findings implicating PTK7 at the crossroads of Wnt signaling pathways in development and disease.
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PTK7 localization and protein stability is affected by canonical wnt ligands
Journal of Cell Science, 2017Co-Authors: Hanna Berger, Marlen Breuer, Hanna Peradziryi, Martina Podleschny, Ralf Jacob, Annette BorchersAbstract:PTK7 (protein tyrosine kinase 7) is an evolutionarily conserved transmembrane receptor with important roles in embryonic development and disease. Originally identified as a gene upregulated in colon cancer it was later shown to regulate planar cell polarity (PCP) and directional cell movement. PTK7 is a Wnt co-receptor, however its role in Wnt signaling remains controversial. Here, we find evidence that place PTK7 at the intersection of canonical and non-canonical Wnt signaling pathways. In presence of canonical Wnt ligands PTK7 is subject to caveolin-mediated endocytosis, while it is unaffected by non-canonical Wnt ligands. PTK7 endocytosis is dependent on the presence of the PTK7 co-receptor Fz7 and results in lysosomal degradation of PTK7. As we previously observed that PTK7 activates non-canonical PCP Wnt signaling but inhibits canonical Wnt signaling, our data suggest a mutual inhibition of canonical and PTK7 Wnt signaling. PTK7 likely suppresses canonical Wnt signaling by binding canonical Wnt ligands thereby preventing their interaction with Wnt receptors supporting canonical Wnt signaling. Conversely, if canonical Wnt proteins interact with the PTK7 receptor they induce its internalization and degradation.
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a PTK7 ror2 co receptor complex affects xenopus neural crest migration
PLOS ONE, 2015Co-Authors: Martina Podleschny, Hanna Berger, Anita Grund, Erik Rollwitz, Annette BorchersAbstract:Neural crest cells are a highly migratory pluripotent cell population that generates a wide array of different cell types and failure in their migration can result in severe birth defects and malformation syndromes. Neural crest migration is controlled by various means including chemotaxis, repellent guidance cues and cell-cell interaction. Non-canonical Wnt PCP (planar cell polarity) signaling has previously been shown to control cell-contact mediated neural crest cell guidance. PTK7 (protein tyrosine kinase 7) is a transmembrane pseudokinase and a known regulator of Wnt/PCP signaling, which is expressed in Xenopus neural crest cells and required for their migration. PTK7 functions as a Wnt co-receptor; however, it remains unclear by which means PTK7 affects neural crest migration. Expressing fluorescently labeled proteins in Xenopus neural crest cells we find that PTK7 co-localizes with the Ror2 Wnt-receptor. Further, co-immunoprecipitation experiments demonstrate that PTK7 interacts with Ror2. The PTK7/Ror2 interaction is likely relevant for neural crest migration, because Ror2 expression can rescue the PTK7 loss of function migration defect. Live cell imaging of explanted neural crest cells shows that PTK7 loss of function affects the formation of cell protrusions as well as cell motility. Co-expression of Ror2 can rescue these defects. In vivo analysis demonstrates that a kinase dead Ror2 mutant cannot rescue PTK7 loss of function. Thus, our data suggest that Ror2 can substitute for PTK7 and that the signaling function of its kinase domain is required for this effect.
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A PTK7/Ror2 Co-Receptor Complex Affects Xenopus Neural Crest Migration
PLOS ONE, 2015Co-Authors: Martina Podleschny, Hanna Berger, Anita Grund, Erik Rollwitz, Annette BorchersAbstract:Neural crest cells are a highly migratory pluripotent cell population that generates a wide array of different cell types and failure in their migration can result in severe birth defects and malformation syndromes. Neural crest migration is controlled by various means including chemotaxis, repellent guidance cues and cell-cell interaction. Non-canonical Wnt PCP (planar cell polarity) signaling has previously been shown to control cell-contact mediated neural crest cell guidance. PTK7 (protein tyrosine kinase 7) is a transmembrane pseudokinase and a known regulator of Wnt/PCP signaling, which is expressed in Xenopus neural crest cells and required for their migration. PTK7 functions as a Wnt co-receptor; however, it remains unclear by which means PTK7 affects neural crest migration. Expressing fluorescently labeled proteins in Xenopus neural crest cells we find that PTK7 co-localizes with the Ror2 Wnt-receptor. Further, co-immunoprecipitation experiments demonstrate that PTK7 interacts with Ror2. The PTK7/Ror2 interaction is likely relevant for neural crest migration, because Ror2 expression can rescue the PTK7 loss of function migration defect. Live cell imaging of explanted neural crest cells shows that PTK7 loss of function affects the formation of cell protrusions as well as cell motility. Co-expression of Ror2 can rescue these defects. In vivo analysis demonstrates that a kinase dead Ror2 mutant cannot rescue PTK7 loss of function. Thus, our data suggest that Ror2 can substitute for PTK7 and that the signaling function of its kinase domain is required for this effect.
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the many roles of PTK7 a versatile regulator of cell cell communication
Archives of Biochemistry and Biophysics, 2012Co-Authors: Hanna Peradziryi, Nicholas S Tolwinski, Annette BorchersAbstract:PTK7 (protein tyrosine kinase 7) is an evolutionarily conserved transmembrane receptor with functions in various processes ranging from embryonic morphogenesis to epidermal wound repair. Here, we review recent findings indicating that PTK7 is a versatile co-receptor that functions as a molecular switch in Wnt, Semaphorin/Plexin and VEGF signaling pathways. We focus in particular on the role of PTK7 in Wnt signaling, as recent data indicate that PTK7 acts as a Wnt co-receptor, which activates the planar cell polarity pathway, but inhibits canonical Wnt signaling.
Alex Y Strongin - One of the best experts on this subject based on the ideXlab platform.
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abstract 3009 membrane pseudokinase PTK7 regulates metastasis
Cancer Research, 2014Co-Authors: Vladislav S Golubkov, Natalie L. Prigozhina, Yong Zhang, Robert M Hoffman, Alex Y StronginAbstract:Studies by others indicate that the membrane pseudokinase 7 (PTK7) regulates canonical and non-canonical Wnt pathways and controls orientation of cells in a tissue plane (planar cell polarity, PCP). There is still no clear understanding of the PTK7 role in cancer: Is it pro-tumorigenic or anti-tumorigenic? Our live cell imaging and cell invasion studies suggest that full-length PTK7 expressed in HT1080 fibrosarcoma cells inhibits directed cell motility, lamellipodia polarization and cell invasion. Using the fluorescence imaging we demonstrated that the expression of full-length PTK7 in HT1080-RFP cells in nude mice significantly reduces lung colonization (metastasis). The pro-invasive membrane type-1 matrix metalloprotease (MT1-MMP/MMP-14) coupled with an ADAM/ADAMTS family member(s) directly cleave PTK7 at the cell surface and reverse the inhibitory anti-invasive signal of full-length PTK7. Ectodomain proteolysis was a prerequisite for the intramembrane cleavage of the residual fragments of PTK7 by γ-secretase. The resulting C-terminal PTK7 fragment translocated to the cell nucleus. To identify the molecular mechanisms downstream of PTK7 proteolysis, we used genome-wide transcriptional profiling and kinome analysis. Full-length PTK7 and the PTK7 mutants representing the cleaved PTK7 forms differentially regulated the expression of multiple genes and induced signaling pathways associated with cell movement, Wnt signaling and cancer. We believe that the regulation of PTK7 proteolysis opens new possibilities to control Wnt signaling, cancer cell invasion and metastasis. Citation Format: Vladislav Golubkov, Yong Zhang, Natalie Prigozhina, Robert M. Hoffman, Alex Strongin. Membrane pseudokinase PTK7 regulates metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3009. doi:10.1158/1538-7445.AM2014-3009
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protein tyrosine pseudokinase 7 PTK7 directs cancer cell motility and metastasis
Journal of Biological Chemistry, 2014Co-Authors: Vladislav S Golubkov, Natalie L. Prigozhina, Yong Zhang, Robert M Hoffman, Konstantin Stoletov, John D Lewis, Phillip E Schwartz, Alex Y StronginAbstract:Abstract It is well established that widely expressed PTK7 is essential for vertebrate tissue morphogenesis. In cancer, the functionality of PTK7 is selectively regulated by membrane type-1 matrix metalloproteinase (MT1-MMP), ADAMs (a disintegrin domain and metalloproteinases), and γ-secretase proteolysis. Here, we established that the full-length membrane PTK7, its Chuzhoi mutant with the two functional MT1-MMP cleavage sites, and its L622D mutant with the single inactivated MT1-MMP cleavage site differentially regulate cell motility in a two-dimensional versus three-dimensional environment. We also demonstrated that in polarized cancer cells, the levels of PTK7 expression and proteolysis were directly linked to the structure and kinetics of cell protrusions, including lamellipodia and invadopodia. In the functionally relevant and widely accepted animal models of metastasis, mouse and chick embryo models, both the overexpression and knock-out of PTK7 in HT1080 cells abrogated metastatic dissemination. Our analysis of human tissue specimens confirmed intensive proteolysis of PTK7 in colorectal cancer tumors, but not in matching normal tissue. Our results provide convincing evidence that both PTK7 expression and proteolysis, rather than the level of the cellular full-length PTK7 alone, contribute to efficient directional cell motility and metastasis in cancer.
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insights into ectodomain shedding and processing of protein tyrosine pseudokinase 7 PTK7
Journal of Biological Chemistry, 2012Co-Authors: Vladislav S Golubkov, Alex Y StronginAbstract:Abstract The membrane PTK7 pseudokinase, a component of both the canonical and non-canonical/planar cell polarity Wnt pathways, modulates cell polarity and motility in biological processes as diverse as embryo development and cancer cell invasion. To determine the individual proteolytic events and biological significance of the ectodomain shedding in the PTK7 function, we used highly invasive fibrosarcoma HT1080 cells as a model system. Current evidence suggested a likely link between PTK7 shedding and cell invasion in our HT1080 cell model system. We also demonstrated that in HT1080 cells the cleavage of the PTK7 ectodomain by an ADAM proteinase was coupled with the membrane type-1 matrix metalloproteinase (MT1-MMP) cleavage of the PKP621↓LI site in the seventh Ig-like domain of PTK7. Proteolytic cleavages led to the generation of two soluble, N-terminal and of two matching C-terminal, cell-associated fragments of PTK7. This proteolysis was a prerequisite for the intramembrane cleavage of the C-terminal fragments of PTK7 by γ-secretase. γ-Secretase cleavage was predominantly followed by the efficient decay of the resulting C-terminal PTK7 fragment via the proteasome. In contrast, in HT1080 cells, which overexpressed the C-terminal PTK7 fragment, the latter readily entered the nucleus. Our data imply that therapeutic inhibition of PTK7 shedding may be used to slow cancer progression.
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abstract 494 proteolysis of pseudokinase PTK7 controls cancer cell invasion
Cancer Research, 2012Co-Authors: Vladislav S Golubkov, Alex Y StronginAbstract:Deregulated cell motility promotes cancer progression and metastasis, a major cause of cancer patient death. Understanding the molecular mechanisms regulating cell motility in malignancy will facilitate an identification of novel anti-metastatic therapies. Recently, we identified a new mechanism, the proteolytic control of directional cell motility and invasion. The membrane protein tyrosine kinase 7 (PTK7) controls the orientation of cells in a tissue plane (planar cell polarity, PCP) and inhibits cancer cell invasion. The pro-invasive membrane type-1 matrix metalloprotease (MT1-MMP/MMP-14) directly cleaves PTK7 at the cell surface and reverses the inhibitory anti-invasive signal of the full-length PTK7. Thus, PTK7 proteolysis by MT1-MMP turns on cell motility and invasion. This ubiquitous mechanism is conserved in processes as diverse as embryo development and cancer cell invasion. Because both the pro-invasive MT1-MMP and the polarity regulating PTK7 are linked to cancer, the precise understanding of the role of PTK7 proteolysis in cancer progression is important to discover novel therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 494. doi:1538-7445.AM2012-494
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potential relation of aberrant proteolysis of human protein tyrosine kinase 7 PTK7 chuzhoi by membrane type 1 matrix metalloproteinase mt1 mmp to congenital defects
Journal of Biological Chemistry, 2011Co-Authors: Vladislav S Golubkov, Alexander E Aleshin, Alex Y StronginAbstract:Membrane PTK7 pseudo-kinase plays an essential role in planar cell polarity and the non-canonical Wnt pathway in vertebrates. Recently, a new N-ethyl-N-nitrosourea-induced mutant named chuzhoi (chz) was isolated in mice. chz embryos have severe birth defects, including a defective neural tube, defective heart and lung development, and a shortened anterior-posterior body axis. The chz mutation was mapped to the Ala-Asn-Pro tripeptide insertion into the junction region between the fifth and the sixth Ig-like domains of PTK7. Unexpectedly, chz reduced membrane localization of the PTK7 protein. We hypothesized and then proved that the chz mutation caused an insertion of an additional membrane type 1 matrix metalloproteinase cleavage site in PTK7 and that the resulting aberrant proteolysis of chz affected the migratory parameters of the cells. It is likely that aberrations in the membrane type 1 matrix metalloproteinase/PTK7 axis are detrimental to cell movements that shape the body plan and that chz represents a novel model system for increasing our understanding of the role of proteolysis in developmental pathologies, including congenital defects.
Vladislav S Golubkov - One of the best experts on this subject based on the ideXlab platform.
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PTK7 proteolytic fragment proteins function during early xenopus development
Developmental Biology, 2019Co-Authors: Hava Lichtig, Yasmin Cohen, Naama Binnun, Vladislav S Golubkov, Dale FrankAbstract:Abstract Protein Tyrosine Kinase 7 (PTK7) is as a critical regulator of canonical and non-canonical Wnt-signaling during embryonic development and cancer cell formation. Disrupting PTK7 activity perturbs vertebrate nervous system development, and also promotes human cancer formation. Observations in different model systems suggest a complex cross-talk between PTK7 protein and Wnt signaling. During Xenopus laevis nervous system development, we previously showed that PTK7 protein positively regulates canonical Wnt signaling by maintaining optimal LRP6 protein levels, but PTK7 also acts in concert with LRP6 protein to repress non-canonical Wnt activity. PTK7 is a transmembrane protein, but studies in cancer cells showed that PTK7 undergoes “shedding” by metalloproteases to different proteolytic fragments. Some PTK7 proteolytic fragments are oncogenic, being localized to alternative cytoplasmic and nuclear cell compartments. In this study we examined the biological activity of two proteolytic carboxyl-terminal PTK7 proteolytic fragments, cPTK7 622–1070 and cPTK7 726–1070 during early Xenopus nervous system development. We found that these smaller PTK7 proteolytic fragments have similar activity to full-length PTK7 protein to promote canonical Wnt-signaling via regulation of LRP6 protein levels. In addition to cancer systems, this study shows in vivo proof that these smaller PTK7 proteolytic fragments can recapitulate full-length PTK7 protein activity in diverse systems, such as vertebrate nervous system development.
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Abstract 5002: Abstract Submission
Cancer Research, 2015Co-Authors: Swati Acharya, Vladislav S Golubkov, Peter K. Jackson, Kira Y.d Petersen, Mandy Kwong, Christopher M. Adams, David B. LewisAbstract:Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Protein tyrosine kinase 7 (PTK7), a catalytically inactive receptor tyrosine kinase (RTK) that is highly expressed by T-lineage cells during intrathymic development, is a novel marker for human CD4+ recent thymic emigrants (RTEs), and is also highly expressed on some T-lineage thymomas, e.g., Jurkat cells as well as inprimary T-Acute Lymphoblastic leukemia. The function of PTK7 in normal human T-cell development and in oncogenesis remains unclear. Here, using RNAi-mediated gene silencing in T-lineage tumor cells, primary human peripheral T-cells, and thymocytes, we found that targeting PTK7 consistently decreased cell survival by augmenting caspase-3 activation of apoptosis. The PTK7 knockdown also decreased AKT phosphorylation and PI3 kinase activity, suggesting an essential role for PTK7 in survival of RTEs and developing thymocytes involving the PI3K/AKT pathway. Using mass spectrometry we identified insulin-like growth factor-1 (IGF-1) receptor as an active kinase partner of PTK7. This interaction was biologically relevant in that PTK7 downregulation also reduced IGF-1R-dependent survival signals in T-lineage cells. As enhanced IGF-1-dependent signaling is a frequent event in oncogenesis, the intersection of PTK7 with the IGF-1 signaling pathway suggests the potential of PTK7-directed therapy of T-lineage tumors. Citation Format: Swati Acharya, Kira Y.D Petersen, Vladislav Golubkov, Mandy Kwong, Christopher M. Adams, Peter K. Jackson, David B. Lewis. Abstract Submission. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5002. doi:10.1158/1538-7445.AM2015-5002
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abstract 3009 membrane pseudokinase PTK7 regulates metastasis
Cancer Research, 2014Co-Authors: Vladislav S Golubkov, Natalie L. Prigozhina, Yong Zhang, Robert M Hoffman, Alex Y StronginAbstract:Studies by others indicate that the membrane pseudokinase 7 (PTK7) regulates canonical and non-canonical Wnt pathways and controls orientation of cells in a tissue plane (planar cell polarity, PCP). There is still no clear understanding of the PTK7 role in cancer: Is it pro-tumorigenic or anti-tumorigenic? Our live cell imaging and cell invasion studies suggest that full-length PTK7 expressed in HT1080 fibrosarcoma cells inhibits directed cell motility, lamellipodia polarization and cell invasion. Using the fluorescence imaging we demonstrated that the expression of full-length PTK7 in HT1080-RFP cells in nude mice significantly reduces lung colonization (metastasis). The pro-invasive membrane type-1 matrix metalloprotease (MT1-MMP/MMP-14) coupled with an ADAM/ADAMTS family member(s) directly cleave PTK7 at the cell surface and reverse the inhibitory anti-invasive signal of full-length PTK7. Ectodomain proteolysis was a prerequisite for the intramembrane cleavage of the residual fragments of PTK7 by γ-secretase. The resulting C-terminal PTK7 fragment translocated to the cell nucleus. To identify the molecular mechanisms downstream of PTK7 proteolysis, we used genome-wide transcriptional profiling and kinome analysis. Full-length PTK7 and the PTK7 mutants representing the cleaved PTK7 forms differentially regulated the expression of multiple genes and induced signaling pathways associated with cell movement, Wnt signaling and cancer. We believe that the regulation of PTK7 proteolysis opens new possibilities to control Wnt signaling, cancer cell invasion and metastasis. Citation Format: Vladislav Golubkov, Yong Zhang, Natalie Prigozhina, Robert M. Hoffman, Alex Strongin. Membrane pseudokinase PTK7 regulates metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3009. doi:10.1158/1538-7445.AM2014-3009
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protein tyrosine pseudokinase 7 PTK7 directs cancer cell motility and metastasis
Journal of Biological Chemistry, 2014Co-Authors: Vladislav S Golubkov, Natalie L. Prigozhina, Yong Zhang, Robert M Hoffman, Konstantin Stoletov, John D Lewis, Phillip E Schwartz, Alex Y StronginAbstract:Abstract It is well established that widely expressed PTK7 is essential for vertebrate tissue morphogenesis. In cancer, the functionality of PTK7 is selectively regulated by membrane type-1 matrix metalloproteinase (MT1-MMP), ADAMs (a disintegrin domain and metalloproteinases), and γ-secretase proteolysis. Here, we established that the full-length membrane PTK7, its Chuzhoi mutant with the two functional MT1-MMP cleavage sites, and its L622D mutant with the single inactivated MT1-MMP cleavage site differentially regulate cell motility in a two-dimensional versus three-dimensional environment. We also demonstrated that in polarized cancer cells, the levels of PTK7 expression and proteolysis were directly linked to the structure and kinetics of cell protrusions, including lamellipodia and invadopodia. In the functionally relevant and widely accepted animal models of metastasis, mouse and chick embryo models, both the overexpression and knock-out of PTK7 in HT1080 cells abrogated metastatic dissemination. Our analysis of human tissue specimens confirmed intensive proteolysis of PTK7 in colorectal cancer tumors, but not in matching normal tissue. Our results provide convincing evidence that both PTK7 expression and proteolysis, rather than the level of the cellular full-length PTK7 alone, contribute to efficient directional cell motility and metastasis in cancer.
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insights into ectodomain shedding and processing of protein tyrosine pseudokinase 7 PTK7
Journal of Biological Chemistry, 2012Co-Authors: Vladislav S Golubkov, Alex Y StronginAbstract:Abstract The membrane PTK7 pseudokinase, a component of both the canonical and non-canonical/planar cell polarity Wnt pathways, modulates cell polarity and motility in biological processes as diverse as embryo development and cancer cell invasion. To determine the individual proteolytic events and biological significance of the ectodomain shedding in the PTK7 function, we used highly invasive fibrosarcoma HT1080 cells as a model system. Current evidence suggested a likely link between PTK7 shedding and cell invasion in our HT1080 cell model system. We also demonstrated that in HT1080 cells the cleavage of the PTK7 ectodomain by an ADAM proteinase was coupled with the membrane type-1 matrix metalloproteinase (MT1-MMP) cleavage of the PKP621↓LI site in the seventh Ig-like domain of PTK7. Proteolytic cleavages led to the generation of two soluble, N-terminal and of two matching C-terminal, cell-associated fragments of PTK7. This proteolysis was a prerequisite for the intramembrane cleavage of the C-terminal fragments of PTK7 by γ-secretase. γ-Secretase cleavage was predominantly followed by the efficient decay of the resulting C-terminal PTK7 fragment via the proteasome. In contrast, in HT1080 cells, which overexpressed the C-terminal PTK7 fragment, the latter readily entered the nucleus. Our data imply that therapeutic inhibition of PTK7 shedding may be used to slow cancer progression.
Jeanpaul Borg - One of the best experts on this subject based on the ideXlab platform.
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PTK7 deficient mice have decreased hematopoietic stem cell pools as a result of deregulated proliferation and migration
Journal of Immunology, 2016Co-Authors: Anne Catherine Lhoumeau, Sylvie Marchetto, Frédérique Lembo, Marilyn Giordano, Marielaure Arcangeli, Maria De Grandis, Jeanchristophe Orsoni, Florence Bardin, Michel Aurrandlions, Jeanpaul BorgAbstract:Hematopoietic stem cells (HSCs) located in adult bone marrow or fetal liver in mammals produce all cells from the blood system. At the top of the hierarchy are long-term HSCs endowed with lifelong self-renewal and differentiation properties. These features are controlled through key microenvironmental cues and regulatory pathways, such as Wnt signaling.We showed previously that PTK7, a tyrosine kinase receptor involved in planar cell polarity, plays a role in epithelial Wnt signaling; however, its function in hematopoiesis has remained unexplored. In this article, we show that PTK7 is expressed by hematopoietic stem and progenitor cells, with the highest level of protein expression found on HSCs. Taking advantage of a PTK7-deficient mouse strain, we demonstrate that loss of PTK7 leads to a diminished pool of HSCs but does not affect in vitro or in vivo hematopoietic cell differentiation. This is correlated with increased quiescence and reduced homing abilities of PTK7-deficient hematopoietic stem and progenitor cells, unraveling novel and unexpected functions for planar cell polarity pathways in HSC fate.
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the PTK7 and ror2 protein receptors interact in the vertebrate wnt planar cell polarity pcp pathway
Journal of Biological Chemistry, 2015Co-Authors: Sebastien Martinez, Avais M Daulat, Anne Catherine Lhoumeau, Virginie Thomé, Pierluigi Scerbo, Marilyn Giordano, Laurent Kodjabachian, Jeanpaul BorgAbstract:The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. Here we show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells. We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, PTK7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that PTK7 is required for papc activation induced by Wnt5a. Interestingly, we find that Wnt5a stimulates the release of the tagged PTK7 intracellular domain, which can translocate into the nucleus and activate papc expression. This study reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements.
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The PTK7 and ROR2 Protein Receptors Interact in the Vertebrate WNT/Planar Cell Polarity (PCP) Pathway
Journal of Biological Chemistry, 2015Co-Authors: Sebastien Martinez, Avais M Daulat, Anne Catherine Lhoumeau, Virginie Thomé, Pierluigi Scerbo, Marilyn Giordano, Laurent Kodjabachian, Jeanpaul BorgAbstract:The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. Here we show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells. We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, PTK7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that PTK7 is required for papc activation induced by Wnt5a. Interestingly, we find that Wnt5a stimulates the release of the tagged PTK7 intracellular domain, which can translocate into the nucleus and activate papc expression. This study reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements.
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the PTK7 receptor family
2015Co-Authors: Anne Catherine Lhoumeau, T Prebet, Sebastien Martinez, Jeanpaul BorgAbstract:PTK7 represents the only member of its family. It has a classical RTK structure with an extracellular domain, a transmembrane domain, and an intracellular domain. However, this domain lacks catalytic activity and therefore PTK7 also belongs to the pseudokinase group. PTK7 is processed by metalloproteinases MT1-MPP and ADAMs and sequentially by γ-secretase. No ligand has been identified to date.
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PTK7 a cell polarity receptor with multiple facets
Cell Cycle, 2011Co-Authors: Anne Catherine Lhoumeau, Francesca Puppo, Thomas Prebet, Laurent Kodjabachian, Jeanpaul BorgAbstract:PTK7 is a tyrosine kinase receptor implicated in planar cell polarity, a process with multiple implications at the cellular and organism levels. Loss of function of PTK7 leads to profound morphogenetic defects in the mouse, such as neural tube defects, misorientation of stereocilia in the inner ear, and impaired polarized cell movements. The planar cell polarity pathway is classically assigned to a non-canonical Wnt pathway, which does not rely on b-catenin transcriptional activity. We recently revealed that PTK7 is implicated in b-catenin-dependent developmental processes in mammalian and Xenopus systems. Based on data recently obtained by our group as well as others, we discuss how PTK7 could be involved in canonical and non-canonical Wnt pathways, and which implications are expected from these data in physiology and physiopathology.
Anne Catherine Lhoumeau - One of the best experts on this subject based on the ideXlab platform.
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PTK7 deficient mice have decreased hematopoietic stem cell pools as a result of deregulated proliferation and migration
Journal of Immunology, 2016Co-Authors: Anne Catherine Lhoumeau, Sylvie Marchetto, Frédérique Lembo, Marilyn Giordano, Marielaure Arcangeli, Maria De Grandis, Jeanchristophe Orsoni, Florence Bardin, Michel Aurrandlions, Jeanpaul BorgAbstract:Hematopoietic stem cells (HSCs) located in adult bone marrow or fetal liver in mammals produce all cells from the blood system. At the top of the hierarchy are long-term HSCs endowed with lifelong self-renewal and differentiation properties. These features are controlled through key microenvironmental cues and regulatory pathways, such as Wnt signaling.We showed previously that PTK7, a tyrosine kinase receptor involved in planar cell polarity, plays a role in epithelial Wnt signaling; however, its function in hematopoiesis has remained unexplored. In this article, we show that PTK7 is expressed by hematopoietic stem and progenitor cells, with the highest level of protein expression found on HSCs. Taking advantage of a PTK7-deficient mouse strain, we demonstrate that loss of PTK7 leads to a diminished pool of HSCs but does not affect in vitro or in vivo hematopoietic cell differentiation. This is correlated with increased quiescence and reduced homing abilities of PTK7-deficient hematopoietic stem and progenitor cells, unraveling novel and unexpected functions for planar cell polarity pathways in HSC fate.
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the PTK7 and ror2 protein receptors interact in the vertebrate wnt planar cell polarity pcp pathway
Journal of Biological Chemistry, 2015Co-Authors: Sebastien Martinez, Avais M Daulat, Anne Catherine Lhoumeau, Virginie Thomé, Pierluigi Scerbo, Marilyn Giordano, Laurent Kodjabachian, Jeanpaul BorgAbstract:The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. Here we show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells. We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, PTK7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that PTK7 is required for papc activation induced by Wnt5a. Interestingly, we find that Wnt5a stimulates the release of the tagged PTK7 intracellular domain, which can translocate into the nucleus and activate papc expression. This study reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements.
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The PTK7 and ROR2 Protein Receptors Interact in the Vertebrate WNT/Planar Cell Polarity (PCP) Pathway
Journal of Biological Chemistry, 2015Co-Authors: Sebastien Martinez, Avais M Daulat, Anne Catherine Lhoumeau, Virginie Thomé, Pierluigi Scerbo, Marilyn Giordano, Laurent Kodjabachian, Jeanpaul BorgAbstract:The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. Here we show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells. We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, PTK7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that PTK7 is required for papc activation induced by Wnt5a. Interestingly, we find that Wnt5a stimulates the release of the tagged PTK7 intracellular domain, which can translocate into the nucleus and activate papc expression. This study reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements.
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overexpression of the promigratory and prometastatic PTK7 receptor is associated with an adverse clinical outcome in colorectal cancer
PLOS ONE, 2015Co-Authors: Anne Catherine Lhoumeau, Sebastien Martinez, Jeanmarie Boher, G Monges, Remy Castellano, Armelle Goubard, Marie Doremus, Flora Poizat, Bernard Lelong, Cecile De ChaisemartinAbstract:Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.
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the PTK7 receptor family
2015Co-Authors: Anne Catherine Lhoumeau, T Prebet, Sebastien Martinez, Jeanpaul BorgAbstract:PTK7 represents the only member of its family. It has a classical RTK structure with an extracellular domain, a transmembrane domain, and an intracellular domain. However, this domain lacks catalytic activity and therefore PTK7 also belongs to the pseudokinase group. PTK7 is processed by metalloproteinases MT1-MPP and ADAMs and sequentially by γ-secretase. No ligand has been identified to date.