Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations

Lorenzi, Matthew V.; Castagnino, Paola; Chen, Qiong; Chedid, Marcio; Miki, Toru

doi:10.1038/sj.onc.1201242

Cited by 27 publications

(22 citation statements)

References 28 publications

(39 reference statements)

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“…Our results, demonstrating that the Ksam-IIC3 receptor, which lacks 54 aa of the C-terminal domain, does not inhibit growth, demonstrate the importance of this domain for the growth inhibitory activity of FGFR2b and confirm the results of previous studies showing that the two receptors may display different biological roles in cell growth, cell transformation and differentiation (Ishii et al, 1995;Lorenzi et al, 1997). These studies showed that the short carboxy-terminal form of the receptor had stronger transformation activity.…”

Section: Discussionsupporting

confidence: 80%

“…Two isoforms of the receptor, FGFR2b and Ksam-IIC3, which differ in the carboxy-terminal domain, have been described and have very different growth-activating properties (Ishii et al, 1995;Lorenzi et al, 1997;Sakaguchi et al, 1999). We therefore investigated the growth inhibitory properties of Ksam-IIC3, the isoform with the short carboxy-terminal domain (Figure 4a).…”

Section: The Distal Carboxy-terminal Portion Of Fgfr2b Is Involved Inmentioning

confidence: 99%

“…The activation of FGFR1 by overexpression has been suggested in a wide variety of cancers, including astrocytoma Yamaguchi et al, 1994), salivary adenocarcinoma (Myoken et al, 1996) and lung carcinoma (Volm et al, 1997;Berger et al, 1999). Splice forms with transforming activity, not expressed in normal tissues, have been reported in gastric cancer for FGFR2 and in pituitary tumours for FGFR4 (Itoh et al, 1994;Ishii et al, 1995;Lorenzi et al, 1997;Ezzat et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor

et al. 2004

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The b isoform of fibroblast growth factor receptor 2, FGFR2b/FGFR2-IIIb/Ksam-IIC1/KGFR, a tyrosine kinase receptor, is expressed in a wide variety of epithelia and is downregulated in several human carcinomas including prostate, salivary and urothelial cell carcinomas. FGFR2b has been shown to inhibit growth in tumour cell lines derived from these carcinomas. Here, we investigated the molecular mechanisms underlying the inhibition of human urothelial carcinoma cell growth following FGFR2b expression. Using a nylon DNA array, we analysed the gene expression profile of the T24 bladder tumour cell line, transfected or not with a construct encoding FGFR2b. The expression of FGFR2b in T24 cells decreased insulin-like growth factor (IGF)-II mRNA levels. This decrease was correlated with a decrease in IGF-II secretion and may have been responsible for the observed inhibition of cell growth because the addition of exogenous IGF-II restored growth rates to normal levels. Using SU5402, an inhibitor of FGFR tyrosine kinase activity, and a kinase dead mutant of the receptor, FGFR2b Y659F/Y660F, we also demonstrated that the growth inhibition and decrease in IGF-II secretion induced by FGFR2b did not require tyrosine kinase activity. Finally, we demonstrated the involvement of the distal carboxy-terminal domain of the receptor in decreasing IGF-II expression and inhibiting T24 cell growth, as Ksam-IIC3, a variant of FGFR2b carrying a short carboxy-terminus, neither downregulated IGF-II nor inhibited cell proliferation. Our data suggest that FGFR2b inhibits the growth of bladder carcinoma cells by reducing IGF-II levels via its carboxy-terminal domain, independent of its tyrosine kinase activity.

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Section: Discussionsupporting

confidence: 80%

Section: The Distal Carboxy-terminal Portion Of Fgfr2b Is Involved Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor

et al. 2004

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“…Furthermore, we and others have previously found that although activating Ras or Raf transforms fibroblasts, only Ras but not Raf transforms epithelial cells, suggesting that distinct mechanisms exist for Ras transformation in epithelial cells and fibroblasts (12,13). The majority of studies have evaluated the transforming potential of FGFR2 IIIb in NIH 3T3 mouse fibroblasts (6,14,15). NIH 3T3 cells express KGF and a KGF monoclonal antibody blocked FGFR2 IIIb C1 transformation of NIH 3T3 cells.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Fibroblast Growth Factor Receptor 2 Isoform Switching in Mammary Oncogenesis

Jiyoung

Lambert

Reuther

et al. 2008

Molecular Cancer Research

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We identified the IIIb C2 epithelial cell -specific splice variant of fibroblast growth factor receptor 2 (FGFR2 IIIb C2) receptor tyrosine kinase in a screen for activated oncogenes expressed in T-47D human breast carcinoma cells. We found FGFR2 IIIb C2 expression in breast carcinoma cell lines and, additionally, expression of the mesenchymal-specific FGFR2 IIIc splice variant in invasive breast carcinomas. FGFR2 IIIc expression was associated with loss of epithelial markers and gain of mesenchymal markers. Although FGFR2 IIIb is expressed in epithelial cells, previous studies on FGFR2 IIIb transformation have focused on NIH 3T3 fibroblasts. Therefore, we compared the transforming activities of FGFR2 IIIb C2 in RIE-1 intestinal cells and several mammary epithelial cells. FGFR2 IIIb C2 caused growth transformation of epithelial cells but morphologic transformation of only NIH 3T3 cells. FGFR2 IIIb C2 -transformed NIH 3T3, but not RIE-1 cells, showed persistent activation of Ras and increased cyclin D1 protein expression. NIH 3T3 but not RIE-1 cells express keratinocyte growth factor, a ligand for FGFR2 IIIb C2. Ectopic treatment with keratinocyte growth factor caused FGFR2 IIIb C2 -dependent morphologic transformation of RIE-1 cells, as well as cyclin D1 up-regulation, indicating that both ligand-independent and stromal cell -derived, ligand-dependent mechanisms contribute to RIE-1 cell transformation. Our results support cell context distinct mechanisms of FGFR2 IIIb C2 transformation. (Mol Cancer Res 2008;6(3):435 -45)

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“…The FGFR2-WT was previously constructed as a chimera consisting of the ectodomain of FGFR2 and the intracellular domain of the wild-type KGFR and represents a wild-type FGFR2 containing two Ig loops and an acidic domain (Lorenzi et al, 1996). KGFR and FGFR2-ET have been described elsewhere (Miki et al, 1991a;Lorenzi et al, 1997). Focus formation assays were performed as described (Miki and Aaronson, 1995).…”

Section: Expression Cloning and Functional Analysis Of Kgfr-pamentioning

confidence: 99%

Identification of a novel activated form of the keratinocyte growth factor receptor by expression cloning from parathyroid adenoma tissue

et al. 1999

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Parathyroid adenomas are benign tumors in the parathyroid glands, whose pathogenesis is largely unknown. We utilized an expression cDNA cloning strategy to identify oncogenes activated in parathyroid adenomas. An expression cDNA library was prepared directly from a clinical sample of parathyroid adenoma tissue, transfected into NIH3T3 cells, and foci of morphologically transformed cells were isolated. Following plasmid rescue, we identi®ed cDNAs for the keratinocyte growth factor receptor at a high frequency. Interestingly, approximately half of the clones encoded a variant receptor containing an altered C-terminus. Analysis of the transforming activity of the variant receptor revealed that the altered C-terminus upregulated the transforming activity in a ligand-independent manner. The higher transforming activity was not accompanied by increase of dimerization or overall autophosphorylation of the receptor. However, tyrosine phosphorylation of downstream receptor substrates, including Shc isoforms and possibly FRS2, are increased in the transfectants expressing the parathyroid tumorderived receptor. Genomic analysis showed that a previously unidenti®ed exon was used to form the novel isoform. This alternative splicing appears to occur preferentially in parathyroid adenomas.

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Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations

Cited by 27 publications

References 28 publications

Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor

Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor

Involvement of Fibroblast Growth Factor Receptor 2 Isoform Switching in Mammary Oncogenesis

Identification of a novel activated form of the keratinocyte growth factor receptor by expression cloning from parathyroid adenoma tissue

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