Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

Roccato, Emanuela; Miranda, Claudia; Ranzi, Valeria; Gishizki, M; Pierotti, Marco A.; Greco, Angela

doi:10.1038/sj.bjc.6600544

Cited by 26 publications

(22 citation statements)

References 36 publications

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“…We have previously observed that the expression of a transfected gene carried by a mammalian expression vector increases if transfected cells are cultured for 10-15 days in the presence of the antibiotic whose resistance gene is on the same vector (Roccato et al, 2002). We were interested in determining whether the TRK-T3 mutants transforming activity might be modulated by the oncoprotein expression level.…”

Section: Transforming Activity Of Mutated Trk-t3 Proteinsmentioning

confidence: 99%

Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation

et al. 2003

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The TRK-T3 oncoprotein, isolated from a human papillary thyroid tumor, arises from the fusion between the N-terminal domain of the TFG gene and the tyrosine kinase domain of the NTRK1 receptor. The 68 kDa TRK-T3 oncoprotein displays a constitutive tyrosine kinase activity resulting in its capability to transform NIH3T3 cells. The TFG portion of TRK-T3 contains a coiled-coil domain, which mediates protein oligomerization essential for the oncogene constitutive activation, and several consensus sites for protein interaction. In this study, we investigate the role of TFG sequences outside the coiledcoil domain on TRK-T3 activation, We constructed four mutants carrying different deletions of TFG sequences and expressed them in mammalian cells. By performing biochemical and biological assays we demonstrated that all the deleted regions are required for TRK-T3 activation, as they are involved in different mechanisms such as protein processing, formation of stable and/or functional complexes, and possible interaction with other proteins. By constructing site-specific mutants, we demonstrated a crucial role for a PB1 domain and a considerable contribution of an SH2-binding motif in TRK-T3 oncogenic activation. This work establishes an important role for TFG sequences outside the coiled-coil domain in the activation of the thyroid TRK-T3 oncogene.

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Section: Transforming Activity Of Mutated Trk-t3 Proteinsmentioning

confidence: 99%

Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation

et al. 2003

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“…Human BRAF-V600E cDNA cloned in the pMCEF vector, kindly donated by Dr R Marais (Wellbrock et al 2004), was subcloned into the pRC-CMV vector. Human RET/PTC1 and TRK-T3 cDNAs were cloned in the pRC-CMV vector (Roccato et al 2002).…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells

Degl’Innocenti¹,

Romeo²,

Tarantino³

et al. 2012

Endocrine-Related Cancer

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Thyroid carcinomas derived from follicular cells comprise papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC) and undifferentiated anaplastic thyroid carcinoma (ATC). PTC, the most frequent thyroid carcinoma histotype, is associated with gene rearrangements that generate RET/PTC and TRK oncogenes and with BRAF-V600E and RAS gene mutations. These last two genetic lesions are also present in a fraction of PDTCs. The ERK1/2 pathway, downstream of the known oncogenes activated in PTC, has a central role in thyroid carcinogenesis. In this study, we demonstrate that the BRAF-V600E, RET/PTC, and TRK oncogenes upregulate the ERK1/2 pathway's attenuator cytoplasmic dual-phase phosphatase DUSP6/MKP3 in thyroid cells. We also show DUSP6 overexpression at the mRNA and protein levels in all the analysed PTC cell lines. Furthermore, DUSP6 mRNA was significantly higher in PTC and PDTC in comparison with normal thyroid tissues both in expression profile datasets and in patients' surgical samples analysed by real-time RT-PCR. Immunohistochemical and western blot analyses showed that DUSP6 was also overexpressed at the protein level in most PTC and PDTC surgical samples tested, but not in ATC, and revealed a positive correlation trend with ERK1/2 pathway activation. Finally, DUSP6 silencing reduced the neoplastic properties of four PTC cell lines, thus suggesting that DUSP6 may have a pro-tumorigenic role in thyroid carcinogenesis.

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“…The ability of the TRK-T3 oncogene to stimulate cell proliferation in a ligand-independent manner is well-documented. The TFG portion of TRK-T3 contains a coiled-coil domain most likely responsible for the constitutive, ligand-independent activation of the receptor tyrosine kinase activity (Roccato et al, 2002). Further mapping of the TFG sequence of TRK-T3 revealed binding motifs for PKC, CK2 and SH3 (Mencinger et al, 1997), which could activate cell survival pathways.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, it has been reported that TRK-T3 has transforming activity on NIH 3T3 cells (Roccato et al, 2002), whereas elevated expression of CDK4 collaborates with an activated RAS oncogene in epidermal tumorigenesis (Lazarov et al, 2002). To investigate as to which of the two cDNAs present in tumor M2 was responsible for the induction of tumorigenic capacity in immunocompetent mice, we expressed TRK-T3 and DCDK4 separately in Ad5/12-transformed Balb/c MEFs by retroviral transduction.…”

Section: Trk-t3 Expression Enhances Tumorigenicitymentioning

confidence: 99%

An in vivo functional genetic screen reveals a role for the TRK-T3 oncogene in tumor progression

et al. 2004

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Over the past decades, much has been learnt about the genes that contribute to oncogenic transformation of primary cells in vitro. However, much less is known about the genes that contribute to the later stages of tumor progression, in which cells of ever increasing malignancy arise through clonal selection in vivo. To search for genes that confer a tumor progression phenotype in vivo, we have used a functional genetic approach. We used adenovirus-transformed mouse embryo fibroblasts, which are tumorigenic in immunodeficient nude mice, but not in immunocompetent mice, due to strong cytotoxic T-cellmediated immune rejection. We infected these cells in vitro with several high-complexity retroviral cDNA expression libraries and selected rare variants that formed tumors in immunocompetent mice. Using this approach, we identify here the TRK-T3 oncogene as a tumor progression gene. TRK-T3 does not inhibit T-cell reactivity towards the tumor cells. Instead, we find that cells expressing TRK-T3 enhances in vivo growth rate, most likely by stimulating anchorage-independent proliferation in growth factor-limiting conditions. Our data indicate that cDNA expression libraries can be used to identify tumor progression genes in vivo that cannot be readily identified using in vitro cell culture systems.

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Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

Cited by 26 publications

References 36 publications

Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation

Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation

DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells

An in vivo functional genetic screen reveals a role for the TRK-T3 oncogene in tumor progression

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