Fyn is a downstream target of the pleiotrophin/receptor protein tyrosine phosphatase β/ζ-signaling pathway: Regulation of tyrosine phosphorylation of Fyn by pleiotrophin

Pariser, Harold; Ezquerra, Laura; Herradón, Gonzalo; Pérez-Piñera, Pablo; Deuel, Thomas F.

doi:10.1016/j.bbrc.2005.05.007

Cited by 92 publications

(79 citation statements)

References 39 publications

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“…The RPTPB receptor was found to be involved in PTN-induced cell migration and neurite outgrowth (35). Binding of PTN to RPTPB was shown to inactivate the catalytic phosphatase activity, leading to further activation of the Src/Fyn kinase family and h-catenin phosphorylation pathway (36). In keeping with this hypothesis, we found that PTND111-136 did not affect the proliferation of PC3 cells and thus believe that the autocrine PTN signaling loop is very marginal because these cells do not exhibit high PTN level or the major cell surface tyrosine kinaselinked receptor such as ALK or RPTPB.…”

Section: Discussionmentioning

confidence: 99%

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

Ducès

Karaky

Martel-Renoir

et al. 2008

Molecular Cancer Therapeutics

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Pleiotrophin (PTN) is a 136-amino acid secreted heparinbinding protein that is considered as a rate-limiting growth and an angiogenic factor in the onset, invasion, and metastatic process of many tumors. Its mitogenic and tumorigenic activities are mediated by the COOH-terminal residues 111 to 136 of PTN, allowing it to bind to cell surface tyrosine kinase-linked receptors. We investigated a new strategy consisting in evaluating the antitumor effect of a truncated PTN, lacking the COOH-terminal 111 to 136 portion of the molecule (PTN#111-136), which may act as a dominant-negative effector for its mitogenic, angiogenic, and tumorigenic activities by heterodimerizing with the wild-type protein. In vitro studies showed that PTN#111-136 selectively inhibited a PTN-dependent MDA-MB-231 breast tumor and endothelial cell proliferation and that, in MDA-MB-231 cells expressing PTN#111-136, the vascular endothelial growth factor-A and hypoxia-inducible factor-1A mRNA levels were significantly decreased by 59% and 71%, respectively, compared with levels in wild-type cells. In vivo, intramuscular electrotransfer of a plasmid encoding a secretable form of PTN#111-136 was shown to inhibit MDA-MB-231 tumor growth by 81%. This antitumor effect was associated with the detection of the PTN#111-136 molecule in the muscle and tumor extracts, the suppression of neovascularization within the tumors, and a decline in the Ki-67 proliferative index. Because PTN is rarely found in normal tissue, our data show that targeted PTN may represent an attractive and new therapeutic approach to the fight against cancer.

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Section: Discussionmentioning

confidence: 99%

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

Ducès

Karaky

Martel-Renoir

et al. 2008

Molecular Cancer Therapeutics

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“…In these cases, because the malignant cells constitutively express Ptn, the malignant cells have a ''stable EMT'' or perhaps more appropriately, an ''arrested EMT.'' Pleiotrophin signals through inactivation of the endogenous protein tyrosine phosphatase activity of RPTP␤͞ ; it increases tyrosine phosphorylation of the different substrates of RPTP␤͞ through the persistent activity of tyrosine kinases acting at the same sites as RPTP␤͞ (2)(3)(4)(5). Pleiotrophin was the first natural ligand to be discovered for this class of receptor-type transmembrane tyrosine phosphatases (2) and the PTN͞RPTP␤͞ signaling pathway triggered by PTN is unique.…”

Section: Discussionmentioning

confidence: 99%

Pleiotrophin disrupts calcium-dependent homophilic cell–cell adhesion and initiates an epithelial–mesenchymal transition

Pérez-Piñera

Alcántara

Dimitrov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of the levels of tyrosine phosphorylation is essential to maintain the functions of proteins in different signaling pathways and other cellular systems, but how the steady-state levels of tyrosine phosphorylation are coordinated in different cellular systems to initiate complex cellular functions remains a formidable challenge. The receptor protein tyrosine phosphatase (RPTP)␤͞ is a transmembrane tyrosine phosphatase whose substrates include proteins important in intracellular and transmembrane proteinsignaling pathways, cytoskeletal structure, cell-cell adhesion, endocytosis, and chromatin remodeling. Pleiotrophin (PTN the protein and Ptn the gene) is a ligand for RPTP␤͞ ; PTN inactivates RPTP␤͞ , leaving unchecked the continued endogenous activity of tyrosine kinases that increase phosphorylation of the substrates of RPTP␤͞ at sites dephosphorylated by RPTP␤͞ in cells not stimulated by PTN. Thus, through the regulation of the tyrosine phosphatase activity of RPTP␤͞ , the PTN͞RPTP␤͞ signaling pathway coordinately regulates the levels of tyrosine phosphorylation of proteins in many cellular systems. We now demonstrate that PTN disrupts cytoskeletal protein complexes, ablates calcium-dependent homophilic cell-cell adhesion, stimulates ubiquitination and degradation of N-cadherin, reorganizes the actin cytoskeleton, and induces a morphological epithelial-mesenchymal transition (EMT) in PTN-stimulated U373 cells. The data suggest that increased tyrosine phosphorylation of the different substrates of RPTP␤͞ in PTN-stimulated cells alone is sufficient to coordinately stimulate the different functions needed for an EMT; it is possible that PTN initiates an EMT in cells at sites where PTN is expressed in development and in malignant cells that inappropriately express Ptn.T he balanced activities of tyrosine kinases and tyrosine phosphatases dynamically regulate the steady-state levels of tyrosine phosphorylation of key proteins essential for many important cellular functions. The regulated disruption of this balance through growth factor and͞or cytokine-activated receptor-transduced signals is an important mechanism of signal transduction but, when deregulated, is a mechanism frequently underlying different diseases and a major feature in the pathogenesis of many human malignancies (1). An important gap, however, is in understanding the mechanism of how different pathways and systems are coordinated to initiate the many different cellular functions required for normal cellular homeostasis, proliferation, and differentiation of cells.The diverse substrates of the receptor protein tyrosine phosphatase (RPTP)␤͞ (2) include ␤-catenin (2), ␤-adducin (3, 4), Fyn (5), GIT1͞Cat-1 (6), and P190RhoGAP (7), indicating that RPTP␤͞ is promiscuous in substrate specificity, but through its activity, is critically positioned to coordinately regulate the steady-state levels of tyrosine phosphorylation of proteins in different signaling networks and cellular systems. Pleiotrophin (PTN the protein and Ptn the gene) is a secret...

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“…signals through the dimerization and inactivation of RPTP␤/, and the loss of phosphatase activity results in increased tyrosine phosphorylation levels of different substrates, including ␤-catenin (24), ␤-adducin (36, 37), Fyn (38), and GIT1/Cat1 (39). However, our results show that the pleiotrophin-mediated RPTP␤/ inactivation is associated with an inhibition of cell migration and attachment.…”

Section: Opposing Effect Of Pleiotrophin/rptp␤/ and Pleiotrophin/ Synmentioning

confidence: 99%

Loss of Receptor Protein Tyrosine Phosphatase β/ζ (RPTPβ/ζ) Promotes Prostate Cancer Metastasis

Diamantopoulou

Kitsou

Ménashi

et al. 2012

Journal of Biological Chemistry

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Background:The role of pleiotrophin and its receptors RPTP␤/ and Syndecan-3 during tumor metastasis remains unknown. Results: RPTP␤/ knockdown initiates EMT, promotes pleiotrophin-mediated migration and attachment through Syndecan-3 and induces in vivo metastasis. Conclusion: RPTP␤/ plays a suppressor-like role in prostate cancer metastasis. Significance: Boosting RPTP␤/ or attenuating Syndecan-3 signaling pathways may lead to more effective therapeutic strategies in treating prostate cancer metastasis.

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Fyn is a downstream target of the pleiotrophin/receptor protein tyrosine phosphatase β/ζ-signaling pathway: Regulation of tyrosine phosphorylation of Fyn by pleiotrophin

Cited by 92 publications

References 39 publications

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

Pleiotrophin disrupts calcium-dependent homophilic cell–cell adhesion and initiates an epithelial–mesenchymal transition

Loss of Receptor Protein Tyrosine Phosphatase β/ζ (RPTPβ/ζ) Promotes Prostate Cancer Metastasis

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