The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis

Iuliano, Rodolfo; Pera, Ilaria Le; Cristofaro, C.; Baudi, Francesco; Arturi, Franco; Pallante, Pierlorenzo; Martelli, Marialuisa; Trapasso, Francesco; Chiariotti, Lorenzo; Fusco, Alfredo

doi:10.1038/sj.onc.1207766

Cited by 70 publications

(73 citation statements)

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“…There- Western blot analysis showed that dephosphorylation of c-Src tyrosine 529, and FAK and paxillin tyrosine phosphorylation in PC MPSV cells are proportional to the levels of r-PTPZ expression. These results have important implications for tumor biology because of the loss of heterozygosity of PTPRJ, the human homolog of r-PTPZ, found in several colon, lung, breast and thyroid cancers (Ruivenkamp et al, 2002;Iuliano et al 2004). Finally, very recently, DEP1/PTPRJ expression levels were found to be drastically reduced or absent also in human pancreatic cancer cells .…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, in a recent paper (Massa et al, 2004), the correlation between the expression of r-PTPZ and the responsivity to the antiproliferative effects of the somatostatin has been demonstrated in glioma cells, indicating that the expression levels of r-PTPZ are also critical in other r-PTPZ-dependent pathways. In addition, it has been suggested that PTPRJ polymorphisms differ in their tumor suppressor activity (Ruivenkamp et al, 2002;Iuliano et al 2004), and it would be intriguing to find whether distinct PTPRJ forms exert different effects on the pathway described herein.…”

Section: Discussionmentioning

confidence: 99%

“…HPTPZ/DEP-1 is upregulated in some cell lines as cell density increases (Ostman et al, 1994;Iuliano et al, 2003), and it inhibits the growth of breast cancer cell lines (Keane et al, 1996). Loss of heterozygosity at the locus of this gene is frequent in human colon, lung, breast and thyroid cancers (Ruivenkamp et al, 2002(Ruivenkamp et al, , 2003Iuliano et al 2004). Lastly, the mouse homolog of HPTPZ/DEP-1/PTPRJ gene, Ptprj, is the candidate for the mouse colon cancer susceptibility locus Scc1 (Ruivenkamp et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

et al. 2005

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The expression of the receptor protein tyrosine phosphatase r-PTPg is drastically reduced in rat and human malignant thyroid cells, whereas its restoration reverts the neoplastic phenotype of retrovirally transformed rat thyroid cells. Moreover, reduced levels and loss of heterozygosity of DEP-1, the human homolog of r-PTPg, have been found in many human neoplasias. Here, we report that the r-PTPg protein binds to c-Src in living cells and dephosphorylates the c-Src inhibitory tyrosine phosphorylation site (Tyr 529), thereby increasing c-Src tyrosine kinase activity in malignant rat thyroid cells stably transfected with r-PTPg. Tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin was enhanced in r-PTPg-expressing cells. This was associated with increased adhesion of malignant r-PTPg-transfected thyroid cells vs both untransfected cells and cells stably transfected with an inactive r-PTPg mutant. Treatment of rat thyroid cells with the c-Src inhibitor PP2 decreased cell adhesion to a higher extent in r-PTPg-transfected cells than in mock-transfected or stably transfected cells with the inactive r-PTPg mutant, indicating that r-PTPg regulates cell-substratum adhesion by activating c-Src. Interestingly, the extent of both c-Src dephosphorylation at Tyr 529, FAK and paxillin phosphorylation, and the increased cell adhesion were associated with the degree of r-PTPg expression.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

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“…A considerable Ptprj loss of heterozygosity has been identified in human colon, mammary, lung, and thyroid carcinomas (13,14). Moreover, the Gln 276 Pro Ptprj polymorphism is implicated in susceptibility to various human cancers (11), whereas the Gln 276 Pro, Arg 326 Gln, and Asp 872 Glu polymorphisms have been associated with thyroid carcinoma (15). Ptprj expression was found to be reduced in in vitro-transformed thyroid follicular cells (2) and in primary specimens of human papillary thyroid carcinomas (PTC; ref.…”

Section: )]mentioning

confidence: 99%

The Receptor-Type Protein Tyrosine Phosphatase J Antagonizes the Biochemical and Biological Effects of RET-Derived Oncoproteins

et al. 2006

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Thyroid cancer is frequently associated with the oncogenic conversion of the RET receptor tyrosine kinase. RET gene rearrangements, which lead to the generation of chimeric RET/papillary thyroid carcinoma (PTC) oncogenes, occur in PTC, whereas RET point mutations occur in familial multiple endocrine neoplasia type 2 (MEN2) and sporadic medullary thyroid carcinomas (MTC). We showed previously that the expression of the receptor-type protein tyrosine phosphatase J (PTPRJ) is suppressed in neoplastically transformed follicular thyroid cells. We now report that PTPRJ coimmunoprecipitates with wild-type RET and with the MEN2A-associated RET(C634R) oncoprotein but not with the RET/PTC1 and RET-MEN2B isoforms. Using mutated forms of PTPRJ and RET-MEN2A, we show that the integrity of the respective catalytic domains is required for the PTPRJ/RET-MEN2A interaction. PTPRJ expression induces dephosphorylation of the RET (C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr 1062 and Tyr 905 ). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels. In line with this finding, adoptive PTPRJ expression reduced the oncogenic activity of RET(C634R) in an in vitro focus formation assay of NIH3T3 cells. As expected from the coimmunoprecipitation results, the RET(M918T) oncoprotein, which is associated to MEN2B and sporadic MTC, was resistant to the dephosphorylating activity of PTPRJ. Taken together, these findings identify RET as a novel substrate of PTPRJ and suggest that PTPRJ expression levels may affect tumor phenotype associated with RET/ PTC1 and RET(C634R) mutants. On the other hand, resistance to PTPRJ may be part of the mechanism of RET oncogenic conversion secondary to the M918T mutation. (Cancer Res 2006; 66(12): 6280-7)

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“…In accordance with previous studies, we found a strong linkage disequilibrium between both CD148 Q276P and R326Q polymorphisms. 26 Importantly, our results suggested that CD148 Q276P and R326Q polymorphisms influence the pathogenicity of PF4/H antibodies but not the immune response to heparin because the minor allele frequency was different between HIT and Ab pos patients, but not between Ab neg and Ab pos controls.…”

Section: Discussionmentioning

confidence: 81%

Polymorphisms of protein tyrosine phosphatase CD148 influence FcγRIIA-dependent platelet activation and the risk of heparin-induced thrombocytopenia

Rollin

Pouplard

Gratacap

et al. 2012

Blood

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Heparin-induced thrombocytopenia (HIT)is due primarily to IgG antibodies specific to platelet factor 4/heparin complexes (PF4/Hs) that activate platelets via Fc␥RIIA. CD148 is a protein tyrosine phosphatase that regulates Src kinases and collagen-induced platelet activation. Three polymorphisms affecting CD148 (Q276P, R326Q, and D872E) were studied in HIT patients and 2 control groups, with or without antibodies to PF4/Hs. Heterozygote status for CD148 276P or 326Q alleles was less frequent in HIT patients, suggesting a protective effect of these polymorphisms. Aggregation tests performed with collagen, HIT plasma, and monoclonal antibodies cross-linking Fc␥RIIA showed consistent hyporesponsiveness of platelets expressing the 276P/ 326Q alleles. In addition, platelets expressing the 276P/326Q alleles exhibited a greater sensitivity to the Src family kinases inhibitor dasatinib in response to collagen or ALB6 cross-linking Fc␥RIIA receptors. Moreover, the activatory phosphorylation of Src family kinases was considerably delayed as well as the phosphorylation of Linker for activation of T cells and phospholipase C␥2, 2 major signaling proteins downstream from Fc␥RIIA. In conclusion, this study shows that CD148 polymorphisms affect platelet activation and probably exert a protective effect on the risk of HIT in patients with antibodies to PF4/Hs. (Blood. 2012; 120(6):1309-1316) IntroductionHeparin-induced thrombocytopenia (HIT) results from an atypical immune response to platelet factor 4/heparin complexes (PF4/Hs), with rapid synthesis of platelet-activating IgG antibodies that activate platelets via Fc␥RIIA receptors. 1 The risk of HIT is probably dependent on the intensity of this immune response, because the likelihood of developing thrombocytopenia and thrombotic complications has been related to the plasma levels of IgG antibodies to PF4. 2,3 However, the reasons explaining why only a subset of patients treated with heparin and who develop significant levels of IgG to PF4/Hs will present with HIT remain to be fully defined.Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) are crucial for the regulation of signaling pathways involved in the control of several cellular processes, including immune responses and platelet activation. Dysregulation of the equilibrium between PTK and PTP function can therefore have pathologic consequences. 4,5 Among PTKs, Src family kinases (SFKs) have an important role in regulating immune responses and platelet adhesion, activation, and aggregation. 6 SFKs are essential in the platelet Fc␥RIIA-dependent signaling pathway, and it was recently demonstrated that dasatinib, a SFK inhibitor, prevents platelet activation induced by HIT antibodies. 7 In addition, SFKs are involved in collagen-dependent platelet activation via glycoprotein VI (GPVI). 8 After collagen/GPVI interaction or Fc␥RIIA cross-linking, SFKs induce phosphorylation of conserved tyrosine residues within the immunoreceptor tyrosine-based activation motif, providing a docking site for the tyrosine...

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The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis

Cited by 70 publications

References 29 publications

The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

The Receptor-Type Protein Tyrosine Phosphatase J Antagonizes the Biochemical and Biological Effects of RET-Derived Oncoproteins

Polymorphisms of protein tyrosine phosphatase CD148 influence FcγRIIA-dependent platelet activation and the risk of heparin-induced thrombocytopenia

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