Fibroblast Growth Factor Receptor 3 Lacking the Ig IIIb and Transmembrane Domains Secreted from Human Squamous Cell Carcinoma DJM-1 Binds to FGFs

Terada, Makoto; Shimizu, Akio; Sato, Nobuhiro; Miyakaze, Shinichi; Katayama, Hiroshi; Kurokawa-Seo, Misuzu

doi:10.1006/mcbr.2001.0306

Cited by 14 publications

(14 citation statements)

References 21 publications

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“…FGFRs belong to the receptor tyrosine kinase family and commonly consist of three extracellular immunoglobulin (Ig)-like domains, a single-pass transmembrane domain, and a split-tyrosine kinase domain. Alternative splicing generates a wide array of isoforms of FGFRs with distinct physical and biological characteristics (Dell and Williams, 1992;Ornitz, 2000;Hanneken, 2001;Groth and Lardelli, 2002;Terada et al, 2001;Wilkie et al, 2002). The most common variants, the IIIb or IIIc isoform, are formed by alternative splicing of the carboxy-terminal half of the third Ig domain of FGFR-1, -2, and -3 but not FGFR-4.…”

Section: Introductionmentioning

confidence: 99%

Prox1 Promotes Lineage-specific Expression of Fibroblast Growth Factor (FGF) Receptor-3 in Lymphatic Endothelium: A Role for FGF Signaling in Lymphangiogenesis

Shin

Min

Larrieu-Lahargue³

et al. 2006

MBoC

171

168

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Fibroblast growth factors play important roles in angiogenesis, but their functions in lymphangiogenesis remain poorly understood. The homeodomain transcription factor Prox1 is essential for development of the lymphatic system by specifying lymphatic endothelial cell (LEC) fate. Here, we identify fibroblast growth factor (FGF) receptor (FGFR)-3 as a novel Prox1 target gene. Ectopic overexpression of Prox1 in blood vascular endothelial cells up-regulates FGFR-3. Prox1 induces the expression of the IIIc isoform, which we also found to be the major isoform of FGFR-3 expressed in LECs. This transcriptional activation is mediated by a direct binding of Prox1 to newly identified Prox1-response elements in the FGFR-3 promoter. Consistently, FGFR-3 is up-regulated in Prox1-positive newly formed lymphatic vessels during embryogenesis and its lymphatic-specific expression is maintained throughout development. We also found that FGF-1 and FGF-2 promote proliferation, migration, and survival of cultured LECs without involvement of vascular endothelial cell growth factor receptor-3. We show that FGF-2 binds to low-and high-affinity receptors on LECs and is efficiently internalized and processed. Moreover, functional inhibition of FGFR-3 using small interfering RNA represses LEC proliferation. Together, these results indicate that FGFR-3 is an initial target of Prox1 during the lymphatic cell fate specification and that FGF signaling may play an important role in lymphatic vessel development.

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Section: Introductionmentioning

confidence: 99%

Prox1 Promotes Lineage-specific Expression of Fibroblast Growth Factor (FGF) Receptor-3 in Lymphatic Endothelium: A Role for FGF Signaling in Lymphangiogenesis

Shin

Min

Larrieu-Lahargue³

et al. 2006

MBoC

171

168

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“…6). Previous reports have shown that FGFR3 D8-10 binds to FGF1 and FGF2 (22,23), indicating relaxed ligand-binding specificity compared with FGFR3 IIIb, which mainly binds FGF1. This is presumably due to the loss of the second half of Ig domain III.…”

Section: Discussionmentioning

confidence: 94%

“…Later, reverse transcriptase-PCR (RT-PCR) analysis of FGFR3 in a breast epithelial tumor cell line (MCF-7) showed the presence of another splice variant in which exons 9 and 10 (originally described as exons 7 and 8) were deleted (21). The same isoform was also identified in the human osteosarcoma cell line SaOS-2 and the squamous carcinoma cell line DJM-1 and was shown to be soluble and capable of binding both FGF1 and FGF2 (22,23). Numerous other isoforms have been identified, some of which result in frameshifts and premature termination in exon 10 (24) and others, with deleted domains, which remain in-frame (25,26).…”

Section: Introductionmentioning

confidence: 85%

“…Recent reports have shown that FGFR3 D8-10 is secreted into the culture medium (22,23). To show this effect in NHU cells, we characterized the expression of FGFR3 D8-10 in NHU-TERT cells 1 transduced with pFB-FGFR3 D8-10-FLAG-Hyg (a retroviral expression vector).…”

Section: Fgfr3 Expression Inmentioning

confidence: 99%

“…In response to ligand, wild-type FGFR3 can either stimulate or inhibit cell proliferation depending on cell type (26,28). FGFR3 D8-10 has been predicted to act as a dominant-negative regulator of FGFR3 signaling (22,23) but its function has not yet been fully elucidated. We studied the function of FGFR3 isoforms by expressing them in NHU-TERT cells and analyzing the effect of FGF1 on proliferation rate (Fig.…”

Section: Fgfr3 Expression Inmentioning

confidence: 99%

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Alternative Splicing of Fibroblast Growth Factor Receptor 3 Produces a Secreted Isoform That Inhibits Fibroblast Growth Factor–Induced Proliferation and Is Repressed in Urothelial Carcinoma Cell Lines

et al. 2005

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Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that play key roles in proliferation, differentiation, and tumorigenesis. FGFR3 was identified as the major family member expressed in both normal human urothelium and cultured normal human urothelial (NHU) cells and was expressed as the IIIb isoform. We also identified a splice variant, FGFR3 #8-10, lacking exons encoding the COOH-terminal half of immunoglobulin-like domain III and the transmembrane domain. Previous reports have assumed that this is a cancer-specific splice variant. We showed that FGFR3 #8-10 is a normal transcript in NHU cells and is translated, N-glycosylated, and secreted. Primary urothelium expressed high levels of FGFR3 transcripts. In culture, levels were reduced in actively proliferating cells but increased at confluence and as cells approached senescence. Cells overexpressing FGFR3 IIIb showed FGF1-induced proliferation, which was inhibited by the addition of FGFR3 #8-10. In bladder tumor cell lines derived from aggressive carcinomas, there were significant alterations in the relative expression of isoforms including an overall decrease in the proportion of FGFR3 #8-10 and predominant expression of FGFR3 IIIc in some cases. In summary, alternative splicing of FGFR3 IIIb in NHU cells represents a normal mechanism to generate a transcript that regulates proliferation and in bladder cancer, the ratio of FGFR3 isoforms is significantly altered. (Cancer Res 2005; 65(22): 10441-9)

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Isoforms of Receptors of Fibroblast Growth Factors

Gong

2014

Journal Cellular Physiology

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The breadth and scope of Fibroblast Growth Factor signaling is immense, with documentation of its role in almost every organism and system studied so far. FGF ligands signal through a family of four distinct tyrosine kinase receptors, the FGF receptors (FGFRs). One contribution to the diversity of function and signaling of FGFs and their receptors arises from the numerous alternative splicing variants that have been documented in the FGFR literature. The present review discusses the types and roles of alternatively spliced variants of the FGFR family members and the significant impact of alternative splicing on the physiological functions of five broad classes of FGFR isoforms. Some characterized known regulatory mechanisms of alternative splicing and future directions in studies of FGFR alternative splicing are also discussed. Presence, absence, and/or the combination of specific exons within each FGFR protein impart upon each individual isoform its unique function and expression pattern during normal function and in diseased states (e.g., in cancers and birth defects). A better understanding of the diversity of FGF signaling in different developmental contexts and diseased states can be achieved through increased knowledge of the presence of specific FGFR isoforms and their impact on downstream signaling and functions. Modern high-throughput techniques afford an opportunity to explore the distribution and function of isoforms of FGFR during development and in diseases.

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Fibroblast Growth Factor Receptor 3 Lacking the Ig IIIb and Transmembrane Domains Secreted from Human Squamous Cell Carcinoma DJM-1 Binds to FGFs

Cited by 14 publications

References 21 publications

Prox1 Promotes Lineage-specific Expression of Fibroblast Growth Factor (FGF) Receptor-3 in Lymphatic Endothelium: A Role for FGF Signaling in Lymphangiogenesis

Prox1 Promotes Lineage-specific Expression of Fibroblast Growth Factor (FGF) Receptor-3 in Lymphatic Endothelium: A Role for FGF Signaling in Lymphangiogenesis

Alternative Splicing of Fibroblast Growth Factor Receptor 3 Produces a Secreted Isoform That Inhibits Fibroblast Growth Factor–Induced Proliferation and Is Repressed in Urothelial Carcinoma Cell Lines

Isoforms of Receptors of Fibroblast Growth Factors

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