A confined variable region confers ligand specificity on fibroblast growth factor receptors: implications for the origin of the immunoglobulin fold.

Yayon, Avner; Zimmer, Yitzhak; Shen, Gh; Avivi, Aaron; Yarden, Yosef; Givol, David

doi:10.1002/j.1460-2075.1992.tb05240.x

Cited by 165 publications

(107 citation statements)

References 25 publications

(14 reference statements)

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“…When such events occur near the 5' end of the gene, ligand-binding domains may be a ected resulting in altered ligandbinding speci®cities. In the case of ®broblast growth factor receptor type 2, for example, alternative exon usage in the immunoglobulin-like loop region results in receptor variants with di erent ligand-binding a nities (Miki et al, 1992;Yayon et al, 1992). These transcripts are expressed in a tissue-and developmental stage-speci®c fashion (Orr-Urtreger et al, 1993;McDonald, 1994;Shi et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

The expression of RET and its multiple splice forms in developing human kidney

et al. 1997

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A series of inductive events between two di erent cell groups, the ureteric bud epithelium and metanephric mesenchyme, gives rise to the functional mammalian kidney. These reciprocal inductive interactions involve a number of molecules, one of which is the RET receptor tyrosine kinase. The phenotype of mice lacking functional RET includes kidney agenesis or severe dysgenesis, indicating a requirement for RET in kidney organogenesis. To investigate RET expression in human kidney development, we used a semi-quantitative RT ± PCR-based strategy to examine a panel of kidney RNA samples ranging from 8 ± 24 weeks gestational age. We found RET expression was highest earlier in development (14 weeks) with expression decreasing through to 24 weeks gestation. While three alternative RET transcripts generated by exon skipping at the 5' end of the gene were all detected throughout kidney development, expression of one transcript, RET2/6, where exon 2 was spliced to exon 6, varied relative to full length RET during this period. Levels of RET2/6 were highest at the earliest age of fetal kidney examined (8 weeks) and decreased relative to all other RET transcripts to low adult levels. The period of high expression coincides with a period of rapid bud bifurcation. Thus, it is possible that RET2/6 has a role in the early growth and di erentiation of the human kidney.

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Section: Discussionmentioning

confidence: 99%

The expression of RET and its multiple splice forms in developing human kidney

et al. 1997

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“…However, the importance of this domain was suggested by a report describing the switch in expression of a FGFR2 isoform with three Ig domains in normal brain to a two Ig domain isoform in malignant astrocytomas (Yamaguchi et al, 1994). While the second Ig domain of FGFR2 has been shown to be important for aFGF binding, the third Ig domain of the receptor governs binding of bFGF or KGF (Miki et al, 1992;Yayon et al, 1992). Interestingly, the KGF receptor (KGFR) and FGFR2 proteins arise from alternative splicing of exons encoding the third Ig domain; the carboxyl terminal half of the third Ig domain of FGFR2 contains sequences responsible for high a nity binding of bFGF while the corresponding region in KGFR mediates KGF binding.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1997

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To assess the e ect(s) of the C-terminal domain on FGFR2 function, we engineered a series of mutant FGFR2 cDNAs encoding deletions in the C-terminus of the receptor and compared their growth properties in NIH3T3 ®broblasts. In contrast to FGFR2-WT, receptors with C-terminal truncations induced ligandindependent transformation of NIH3T3 cells and transfectants expressing these mutant receptors eciently formed colonies in semisolid medium. Introduction of point mutations (Y to F) into the C-terminus of FGFR2 at positions 813, 784 or 780 revealed that these mutant receptors also displayed activities similar to that of C-terminally truncated receptors. C-terminally altered FGF receptors did not show an increase in the basal level of receptor phosphorylation compared to that of FGFR2-WT suggesting that elevated receptor phosphorylation does not underlie the transforming activity of these receptors. Interestingly, expression of transforming FGFR2 derivatives, unlike H-Ras transformed cells, did not result in the activation of the mitogen-activated protein kinases (MAPKs), p42/ERK2 and p44/ERK1, indicating that this pathway is not constitutively active in FGFR2-transformed cells. Finally, we report the overexpression of FGFR2 mRNA and protein in several human tumor cell lines suggesting activation of the receptor in these tumors.

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“…The mutually exclusive exons IIIb and IIIc confer ligand-binding specificities. For FGFR2, the IIIb variant (KGFR) bound FGF-1 and KGF with high affinity and FGF-2 binding was minimal, while the IIIc variant (bek) bound FGF-1 and FGF-2 but not KGF (Mansukhani et al, 1992;Miki et al, 1992;Yayon et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Re‐programming of expression of the KGFR and bek variants of fibroblast growth factor receptor 2 during limb regeneration in newts (Notophthalmus viridescens)

Poulin

Chiu

1995

Developmental Dynamics

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We have previously shown, by in situ hybridization, that fibroblast growth factor receptor 2 (FGFRB) is present in the basal layer of wound epithelium during limb regeneration in newts (Notophthalmus viridescens). In contrast, FGFRl expression is observed throughout the blastema mesenchyme but is distinctly absent from the wound epithelium (Poulin et al. [1993] Development 1193534361). Sequence analysis revealed that we have isolated both the KGFR and bek variants of FGFR2. These two variants differ only in the second half of the last of their three (or two) Ig-like domains. In this report, we show the expression patterns of FGFRB variants during limb regeneration by in situ hybridization. During the pre-blastema stages of regeneration, FGFRB expression was observed in the basal layer of the wound epithelium and in the cells of the periosbum. The wound epithelial hybridization was observed when the KGFR-specific probe was used while the bek-specific probe hybridized to mRNA in the cells of the periosteum. As regeneration progresses to the blastema stages, KGFR expression continued to be observed in the basal layer of the wound epithelium with additional hybridization seen in the blastema mesenchyme closely associated with the bisected bones. The bek-specific hybridization pattern observed at this stage corresponds specifically to the mesenchymal hybridization. In the differentiation stages of regeneration, the mesenchymal expression of FGFR2 becomes restricted to the cells of the condensing cartilage and later to the perichondrium. Interestingly, there appears to be a dorsoventral gradient of the expression of both KGFR and bek variants of FGFR2, which are opposite each other at the later stages of regeneration. Thus, re-programming of expression of the two FGFR2 variants is required during the initial wound closure of limb regeneration. Remarkably, the expression patterns of KGFR and bek mimic those observed in the mouse limb bud during early embryonic development (Orr-Urtreger et al. [1993]

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A confined variable region confers ligand specificity on fibroblast growth factor receptors: implications for the origin of the immunoglobulin fold.

Cited by 165 publications

References 25 publications

The expression of RET and its multiple splice forms in developing human kidney

The expression of RET and its multiple splice forms in developing human kidney

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

Re‐programming of expression of the KGFR and bek variants of fibroblast growth factor receptor 2 during limb regeneration in newts (Notophthalmus viridescens)

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