Ret oncogene signal transduction via a IRS-2/PI 3-kinase/PKB and a SHC/Grb-2 dependent pathway: possible implication for transforming activity in NIH3T3 cells

Hennige, Anita M.; Lammers, Reiner; Arlt, Dorit; Höppner, Wolfgang; Strack, Volker; Niederfellner, Gerhard; Seif, F. J.; Häring, Hans‐Ulrich; Kellerer, Monika

doi:10.1016/s0303-7207(00)00283-5

Cited by 28 publications

(24 citation statements)

References 31 publications

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“…In order to explore genomic alterations associated with the development of both inherited and sporadic MTC, a series of MTC from patients carrying either a MEN2A mutation (RET 634 MTC bearing either the RET 634 mutation or a sporadic RET WT showed overexpression of genes related to proliferation and cell survival, as compared with MTC bearing the RET 918 mutation. Some of them are mediated by RET and GDNF family intracellular signaling, such as the IRS2 pathway (Hennige et al 2000) leading to downstream factor activation of signal transducers and activators of a transcription, focal adhesion molecule (FAK), and Fyn, a Src-like kinase (Sariola & Saarma 2003, Panta et al 2004, Plaza Menacho et al 2005. Furthermore, vitronectin receptor integrin (ITGAV) and caveolin (CAV1), two factors involved in the FAK and Fyn stimulation pathways, leading to Ras/MAPK pathway activation and cell proliferation, were also found to be overexpressed (Wary et al 1998, Panta et al 2004, Plaza Menacho et al 2005.…”

Section: Discussionmentioning

confidence: 99%

Aggressive inherited and sporadic medullary thyroid carcinomas display similar oncogenic pathways

Ameur¹,

Lacroix²,

Roucan³

et al. 2009

Endocrine-Related Cancer

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RET oncogene mutations are found in familial medullary thyroid carcinomas (MTC) and in one-third of sporadic cases. Oncogenic mechanisms involved in non-RET mutated sporadic MTC remain unclear. To study alterations associated with the development of both inherited and sporadic MTC, pangenomic DNA microarrays were used to analyze the transcriptome of 13 MTCs (four familial and nine sporadic). By using an ANOVA test, a list of 173 gene sequences with at least a twofold change expression was obtained. A subset of differentially expressed genes was controlled by real-time quantitative PCR and immunohistochemistry on a larger collection of MTCs. The expression pattern of those genes allowed us to distinguish two groups of sporadic tumors. The first group displays an expression profile similar to that expressed by inherited RET634 tumors. The second presents an expression profile close to that displayed by inherited RET918 tumors and includes tumors from patients with distant metastases. It is characterized by the overexpression of genes involved in proliferation and invasion (PTN, ESM1, and CEACAM6) or matrix remodeling (COL1A1, COL1A2, and FAP). Interestingly, RET918 tumors showed overexpression of the PTN gene, encoding pleiotrophin, a protein associated with metastasis. Using a MTC cell line, silencing of RET induced the inhibition of PTN gene expression. Overall, our results suggest that familial MTC and sporadic MTC could activate similar oncogenic pathways.

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Section: Discussionmentioning

confidence: 99%

Aggressive inherited and sporadic medullary thyroid carcinomas display similar oncogenic pathways

Ameur¹,

Lacroix²,

Roucan³

et al. 2009

Endocrine-Related Cancer

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“…IRS-1, in addition to being observed to interact with ␤-catenin, has recently been shown to directly bind, interact, and cooperate with numerous oncogene proteins, including JCV T antigen (21), simian virus 40 T antigen (14), ret oncoprotein (19,32), and the ETV6-NTRK3 translocation oncoprotein (24). Importantly, downregulation of IRS-1 or elimination of its tyrosine phosphorylation can impair transformation by many of these oncogene proteins (8,9,14,21).…”

Section: Discussionmentioning

confidence: 99%

Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2

Dearth

Cui

Kim

et al. 2006

Molecular and Cellular Biology

159

149

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Insulin receptor substrates (IRSs) are signaling adaptors that play a major role in the metabolic and mitogenic actions of insulin and insulin-like growth factors. Reports have recently noted increased levels, or activity, of IRSs in many human cancers, and some have linked this to poor patient prognosis. We found that overexpressed IRS-1 was constitutively phosphorylated in vitro and in vivo and that transgenic mice overexpressing IRS-1 or IRS-2 in the mammary gland showed progressive mammary hyperplasia, tumorigenesis, and metastasis. Tumors showed extensive squamous differentiation, a phenotype commonly seen with activation of the canonical ␤-catenin signaling pathway. Consistent with this, IRSs were found to bind ␤-catenin in vitro and in vivo. IRS-induced tumorigenesis is unique, given that the IRSs are signaling adaptors with no intrinsic kinase activity, and this supports a growing literature indicating a role for IRSs in cancer. This study defines IRSs as oncogene proteins in vivo and provides new models to develop inhibitors against IRSs for anticancer therapy.Insulin receptor substrates (IRSs) are a family of intracellular proteins that integrate and coordinate hormone, cytokine, and growth factor signaling. To date, four IRS proteins (IRS-1 to IRS-4) have been identified (27). All IRSs contain multiple tyrosine phosphorylation sites that act as binding sites for SH2-containing proteins (27). The IRS proteins were first identified as substrates and presumed signaling intermediates of the insulin receptor. However, it is now clear that the IRS proteins can be activated and phosphorylated by a number of other signaling pathways, including those that are critical for mammary gland development, such as growth hormone and prolactin (2, 56).Much research has focused on the roles of IRSs in both metabolic and mitogenic signaling; however, the last several years have seen an emergence of literature implicating IRSs in human cancer. IRS-1 is constitutively active and phosphorylated in many tumors (6). IRS-1 levels are increased in patients with pancreatic cancer (1), and both IRS-1 and IRS-2 levels are increased in patients with hepatocellular cancer (3, 36). We previously reported that high IRS-1 levels are associated with poor outcomes for patients with breast cancer (25, 41), and this is supported by further studies showing that IRS-1 is expressed in patients with primary breast cancer and metastases, and its levels correlate with poor differentiation and lymph node involvement (22). One study, however, found that IRS-1 levels in advanced primary breast cancers were reduced compared to breasts from healthy patients (44).The mouse mammary gland has served as a useful area for the identification and characterization of oncogenes and tumor suppressor genes important in human breast cancer (15). For example, transgenic mice overexpressing the HER-2 oncogene develop mammary cancer with biological and phenotypic variances similar to those observed in human breast cancer patients (23).To date, there have been no re...

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“…In the case of Ret, Tyr586 of Ret/ptc2 (Tyr1062 of protoRet) has been recently proposed to be a multifunctional docking site, binding Shc, Enigma and p85 of PI3K (Arighi et al, 1997;Durick et al, 1996;SegounCariou and Billaud, 2000). However, not even recent studies concerning the Tyr1062 of Ret and the transducer molecules binding this crucial docking site (Segoun-Cariou and Billaud, 2000;Besset et al, 2000;Hennige et al, 2000;Hayashi et al, 2000) have formally demonstrated that Shc is essential for transformation. To better understand the role of Shc, we have therefore constructed the RET/PTC2-N583A mutant.…”

Section: Discussionmentioning

confidence: 99%

Key role of Shc signaling in the transforming pathway triggered by Ret/ptc2 oncoprotein

et al. 2001

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The RET/PTC oncogenes, generated by chromosomal rearrangements in papillary thyroid carcinomas, are constitutively activated versions of protoRET, a gene encoding two protein isoforms of a transmembrane tyrosine kinase receptor. By using Ret/ptc2 short isoform (iso9), we have previously demonstrated that Tyr586 (Tyr1062 of protoRet) is the docking site for both the PTB and the SH2 domains of Shc. To determine the relevance of this interaction for the transforming activity of Ret/ptc oncogenes, we have generated and characterized novel Ret/ptc mutants unable to activate Shc: Ret/ptc2 long isoform (iso51)-Y586F and both isoforms of Ret/ptc2-N583A. These mutants neither activate Shc nor transform NIH3T3 cells. Since Tyr1062 shows features of a multifunctional docking site, we have used a Shc mutant (Shc Y317F) to directly assess Shc role. We have demonstrated that in our cell system Shc Y317F behaves like a dominant interfering mutant on the activation of the Grb2-Sos pathway by endogenous Shc triggered by Ret/ptc2. A strong reduction of the transforming activity of Ret/ptc2 in presence of this mutant was also demonstrated. Our data suggest that Shc activation play a key role in the transforming pathways triggered by Ret/ptc oncoproteins. Moreover, we have shown that coexpression of the Shc-Y317F mutant with Ret/ptc2 speci®cally causes apoptosis, and that the surviving cells lose the long-term expression of one of the two genes. Oncogene (2001) 20, 3475 ± 3485.

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Ret oncogene signal transduction via a IRS-2/PI 3-kinase/PKB and a SHC/Grb-2 dependent pathway: possible implication for transforming activity in NIH3T3 cells

Cited by 28 publications

References 31 publications

Aggressive inherited and sporadic medullary thyroid carcinomas display similar oncogenic pathways

Aggressive inherited and sporadic medullary thyroid carcinomas display similar oncogenic pathways

Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2

Key role of Shc signaling in the transforming pathway triggered by Ret/ptc2 oncoprotein

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