Autocrine transformation by fibroblast growth factor 9 (FGF‐9) and its possible participation in human oncogenesis

Matsumoto-Yoshitomi, Sumie; Habashita, Junko; Nomura, Chisako; Kuroshima, Ken-Ichi; Kurokawa, Tsutomu

doi:10.1002/(sici)1097-0215(19970502)71:3<442::aid-ijc23>3.3.co;2-j

Cited by 11 publications

(14 citation statements)

References 18 publications

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“…Structure Determination-The first 33 N-terminal residues of FGF9 were deleted because they are implicated only in secretion and not FGFR binding (17,26). Truncated FGF9 (residues 35-208) was expressed in E. coli and purified to homogeneity (see "Experimental Procedures").…”

Section: Resultsmentioning

confidence: 99%

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Crystal Structure of Fibroblast Growth Factor 9 Reveals Regions Implicated in Dimerization and Autoinhibition

Plotnikov¹,

Eliseenkova²,

Ibrahimi³

et al. 2001

Journal of Biological Chemistry

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Fibroblast growth factors (FGFs) constitute a large family of heparin-binding growth factors with diverse biological activities. FGF9 was originally described as glia-activating factor and is expressed in the nervous system as a potent mitogen for glia cells. Unlike most FGFs, FGF9 forms dimers in solution with a K d of 680 nM. To elucidate the molecular mechanism of FGF9 dimerization, the crystal structure of FGF9 was determined at 2.2 Å resolution. FGF9 adopts a ␤-trefoil fold similar to other FGFs. However, unlike other FGFs, the N-and C-terminal regions outside the ␤-trefoil core in FGF9 are ordered and involved in the formation of a 2-fold crystallographic dimer. A significant surface area (>2000 Å 2 ) is buried in the dimer interface that occludes a major receptor binding site of FGF9. Thus, we propose an autoinhibitory mechanism for FGF9 that is dependent on sequences outside of the ␤-trefoil core. Moreover, a model is presented providing a molecular basis for the preferential affinity of FGF9 toward FGFR3.The mammalian fibroblast growth factor (FGF) 1 family contains at least 22 distinct polypeptides (FGF1-FGF22) that are expressed in a specific spatial and temporal pattern (1-5). FGFs play important roles in numerous physiological and pathological processes (1-5). Members of the FGF family share between 10 and 55% sequence identity (6). Crystal structures of FGF1 (7), FGF2 (7-9), and FGF7 (10), have revealed a common core FGF structure consisting of three copies of a four-stranded ␤-sheet, known as a ␤-trefoil fold. All FGFs contain N-and C-terminal segments outside the ␤-trefoil core. However, the length of these segments, especially the C termini, varies greatly among different FGFs. In FGF1, FGF2, FGF4, and FGF7, the end of polypeptide chain virtually coincides with the end of the ␤-trefoil fold. Consequently, these FGFs have extremely short C-terminal segments. In contrast, other FGFs, such as FGF3, FGF5, and FGF8, have long C-terminal extensions. The functional relevance of these N-and C-terminal extensions remains uncharacterized. FGF9 (glia-activating factor) was purified as a heparin-binding, secreted glycoprotein from cultured human glioma cell line NMC-G1 (11). FGF9 shows 30% sequence identity with the prototypical FGF family members, FGF1 and FGF2 (12). Purified FGF9 is mitogenic for many types of cultured cells including glia cells, oligodendrocyte type 2 astrocyte progenitor cells, smooth muscle cells, pheochromocytoma PC12 cells, and BALB/3T3 fibroblasts (11). Because FGF9, unlike FGF1 and FGF2, has no effect on human umbilical vein endothelial cells, it is suggested that FGF9 may have a unique receptor specificity (11). In fact, biochemical studies performed utilizing various soluble FGFR-alkaline phosphatase fusion proteins and genetically engineered cells expressing different full-length FGFRs have demonstrated that FGF9 binds preferentially to the IIIc form of FGFR3 (13-15).FGF9, like prototypical FGFs, does not have a typical secretory signal peptide. Yet, it is still glycosylated and...

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Section: Resultsmentioning

confidence: 99%

“…N-terminal sequencing of secreted FGF9 shows that it is missing only the initiation methionine (12,16). It has been suggested that FGF9 secretion is mediated via a noncleaved signal sequence consisting of the first 33 residues (17,18). We have expressed and purified truncated FGF9 (residues in Escherichia coli and observed that it dimerizes in solution.…”

mentioning

confidence: 98%

Crystal Structure of Fibroblast Growth Factor 9 Reveals Regions Implicated in Dimerization and Autoinhibition

Plotnikov¹,

Eliseenkova²,

Ibrahimi³

et al. 2001

Journal of Biological Chemistry

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“…Previous studies have shown FGF9 can transform murine fibroblasts and promote growth of these cells in nude mice (36). Matsumoto-Yoshitomi and colleagues found that transfection of human FGF9 cDNA into BALB/c 3T3 clone A31 cells led to their morphologic transformation, focus formation, growth in soft agar, and tumorigenicity in nude mice.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas

Hendrix¹,

Wu²,

et al. 2006

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Wnt signaling plays a key role in development and adult tissues via effects on cell proliferation, motility, and differentiation. The cellular response to Wnt ligands largely depends on their ability to stabilize B-catenin and the ability of B-catenin to bind and activate T-cell factor (TCF) transcription factors. Roughly 40% of ovarian endometrioid adenocarcinomas (OEA) have constitutive activation of Wnt signaling as a result of oncogenic mutations in the B-catenin protein or inactivating mutations in key negative regulators of B-catenin, such as the adenomatous polyposis coli and Axin tumor suppressor proteins. We used oligonucleotide microarrays to identify genes of which expression was activated in OEAs with B-catenin dysregulation compared with OEAs lacking Wnt/ B-catenin pathway defects. Using microarray and quantitative PCR-based approaches, we found that fibroblast growth factor (FGF9) expression was increased >6-fold in primary OEAs with Wnt/B-catenin pathway defects compared with OEAs lacking such defects. Evidence that B-catenin and TCFs regulate FGF9 expression in several epithelial cell lines was obtained. We found FGF9 was mitogenic for epithelial cells and fibroblasts and FGF9 could stimulate invasion of epithelial and endothelial cells through Matrigel in transwell assays. Furthermore, FGF9 could promote neoplastic transformation of the E1A-immortalized RK3E epithelial cell line, and short hairpin RNA-mediated inhibition of endogenous FGF9 expression in the OEA cell line TOV112D, which carries a B-catenin mutation, inhibited neoplastic growth properties of the cells. Our findings support the notion that FGF9 is a key factor contributing to the cancer phenotype of OEAs carrying Wnt/ B-catenin pathway defects. (Cancer Res 2006; 66(3): 1354-62)

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“…FGF signal play an important role in cellular function, including growth, invasion, and epithelialto-mesenchymal transition(EMT) [14,15]. Mutations or gene amplification of FGFR1, FGFR2, and FGFR3 have been reported in different kinds of solid cancers [16][17][18][19].…”

Section: Discussionmentioning

confidence: 99%

Introducing, OncoTarget

Blagosklonny¹,

Gudkov²

2010

Oncotarget

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Fibroblast growth factor (FGF) 9 is a member of the FGF family, which promotes carcinogenesis in some solid tumours. However, its biological and prognostic significance in gastric cancer (GC) is unclear. We examined FGF9 expression in 180 GC and corresponding non-tumorous gastric tissue samples by immunohistochemistry and evaluated its role in predicting tumour prognosis. Knockdown of FGF9 by siRNA inhibited cell growth and induced apoptosis in GC cell lines. Fifty of the 180 GC specimens (27.8%) had high FGF9 protein expression, whereas decreased or unchanged expression was observed in 130 cases (72.2%). High FGF9 expression was a significant predictor of poor survival (28.1 vs. 55.8 months, P < 0.001). After stratification according to AJCC stage, FGF9 remained a significant predictor of shorter survival in stage II (30.6 vs. 64.9 months, P < 0.001) and stage III GC (29.7 vs. 58.9 months, P < 0.001). Multivariate and univariate analysis showed that higher expression of FGF9 can be used as a predictor for poor prognosis (HR, 2.95; 95% CI, 1.97-4.41; P < 0.001; and HR, 2.94; 95% CI, 2.01-4.31; P < 0.001, respectively). FGF9 may provide the anti-apoptotic function and be useful as a novel independent marker for evaluating GC prognosis

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Autocrine transformation by fibroblast growth factor 9 (FGF‐9) and its possible participation in human oncogenesis

Cited by 11 publications

References 18 publications

Crystal Structure of Fibroblast Growth Factor 9 Reveals Regions Implicated in Dimerization and Autoinhibition

Crystal Structure of Fibroblast Growth Factor 9 Reveals Regions Implicated in Dimerization and Autoinhibition

Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas

Introducing, OncoTarget

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