The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2413-2419 ◽  
Author(s):  
Zhihua Li ◽  
Yuan Xiao Zhu ◽  
Elizabeth E. Plowright ◽  
P. Leif Bergsagel ◽  
Marta Chesi ◽  
...  
Keyword(s):  
Growth Factor ◽  
B Cell ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
B Cell Lymphoma ◽  
Cell Phenotype ◽  
Mutant Form ◽  
Fibroblast Growth ◽  
Wild Type

Abstract Translocations involving fibroblast growth factor receptor 3 (fgfr3) have been identified in about 25% of patients with myeloma. To directly examine the oncogenic potential offgfr3, murine bone marrow (BM) cells were transduced with retroviral vectors containing either wild-type fgfr3 or an activated mutant form of the receptor, fgfr3-TD. Mice transplanted with FGFR3-TD–expressing BM developed a marked leukocytosis and lethal hematopoietic cell infiltration of multiple tissues within 6 weeks of transplantation. Secondary and tertiary recipients of spleen or BM from primary fgfr3-TD mice also developed tumors within 6 to 8 weeks. Analysis of the circulating tumor cells revealed a pre-B-cell phenotype in most mice, although immature T-lymphoid or mature myeloid populations also predominated in some animals. Enhanced lymphoid but not myeloid colony formation was observed in the early posttransplantation period and only interleukin 7 and FGF-responsive pre-B-cell lines could be established from tumors. Cell expansions in primary recipients appeared polyclonal, whereas tumors in later passages exhibited either clonal B- or T-cell receptor gene rearrangements. Mice transplanted with wild-type FGFR3-expressing BM developed delayed pro-B-cell lymphoma/leukemias approximately 1 year after transplantation. These studies confirm that FGFR3 is transforming and can produce lymphoid malignancies in mice.

A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1

1991 ◽  
Vol 11 (10) ◽  
pp. 5068-5078
Author(s):  
M Mohammadi ◽  
A M Honegger ◽  
D Rotin ◽  
R Fischer ◽  
F Bellot ◽  
...  
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Binding Site ◽  
Fibroblast Growth Factor ◽  
Tryptic Peptide ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Sh2 Domain ◽  
Fibroblast Growth ◽  
Wild Type

Phospholipase C-gamma (PLC-gamma) is a substrate of the fibroblast growth factor receptor (FGFR; encoded by the flg gene) and other receptors with tyrosine kinase activity. It has been demonstrated that the src homology region 2 (SH2 domain) of PLC-gamma and of other signalling molecules such as GTPase-activating protein and phosphatidylinositol 3-kinase-associated p85 direct their binding toward tyrosine-autophosphorylated regions of the epidermal growth factor or platelet-derived growth factor receptor. In this report, we describe the identification of Tyr-766 as an autophosphorylation site of flg-encoded FGFR by direct sequencing of a tyrosine-phosphorylated tryptic peptide isolated from the cytoplasmic domain of FGFR expressed in Escherichia coli. The same phosphopeptide was found in wild-type FGFR phosphorylated either in vitro or in living cells. Like other growth factor receptors, tyrosine-phosphorylated wild-type FGFR or its cytoplasmic domain becomes associated with intact PLC-gamma or with a fusion protein containing the SH2 domain of PLC-gamma. To delineate the site of association, we have examined the capacity of a 28-amino-acid tryptic peptide containing phosphorylated Tyr-766 to bind to various constructs containing SH2 and other domains of PLC-gamma. It is demonstrated that the tyrosine-phosphorylated peptide binds specifically to the SH2 domain but not to the SH3 domain or other regions of PLC-gamma. Hence, Tyr-766 and its flanking sequences represent a major binding site in FGFR for PLC-gamma. Alignment of the amino acid sequences surrounding Tyr-766 with corresponding regions of other FGFRs revealed conserved tyrosine residues in all known members of the FGFR family. We propose that homologous tyrosine-phosphorylated regions in other FGFRs also function as binding sites for PLC-gamma and therefore are involved in coupling to phosphatidylinositol breakdown.

scholarly journals Tyrosine 766 in the fibroblast growth factor receptor-1 is required for FGF-stimulation of phospholipase C, phospholipase D, phospholipase A(2), phosphoinositide 3-kinase and cytoskeletal reorganisation in porcine aortic endothelial cells

2000 ◽  
Vol 113 (4) ◽  
pp. 643-651 ◽  
Author(s):  
M.J. Cross ◽  
M.N. Hodgkin ◽  
S. Roberts ◽  
E. Landgren ◽  
M.J. Wakelam ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Wild Type ◽  
Aortic Endothelial Cells ◽  
Phosphoinositide 3 Kinase ◽  
Porcine Aortic Endothelial Cells ◽  
Stimulation Of

Fibroblast growth factor-mediated signalling was studied in porcine aortic endothelial cells expressing either wild-type fibroblast growth factor receptor-1 or a mutant receptor (Y766F) unable to bind phospholipase C-(γ). Stimulation of cells expressing the wild-type receptor resulted in activation of phospholipases C, D and A(2) and increased phosphoinositide 3-kinase activity. Stimulation of the wild-type receptor also resulted in stress fibre formation and a cellular shape change. Cells expressing the Y766F mutant receptor failed to stimulate phospholipase C, D and A(2) as well as phosphoinositide 3-kinase. Furthermore, no stress fibre formation or shape change was observed. Both the wild-type and Y766F receptor mutant activated MAP kinase and elicited proliferative responses in the porcine aortic endothelial cells. Thus, fibroblast growth factor receptor-1 mediated activation of phospholipases C, D and A(2) and phosphoinositide 3-kinase was dependent on tyrosine 766. Furthermore, whilst tyrosine 766 was not required for a proliferative response, it was required for fibroblast growth factor receptor-1 mediated cytoskeletal reorganisation.

Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 992-998 ◽  
Author(s):  
Elizabeth E. Plowright ◽  
Zhihua Li ◽  
P. Leif Bergsagel ◽  
Marta Chesi ◽  
Dwayne L. Barber ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Messenger Rna ◽  
Fibroblast Growth Factor Receptor ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Growth Factor Receptor ◽  
Myeloma Cell ◽  
Fibroblast Growth ◽  
Wild Type

The t(4;14) translocation occurs in 25% of multiple myeloma (MM) and results in both the ectopic expression of fibroblast growth factor receptor 3 (FGFR3) from der4 and immunoglobulin heavy chain-MMSET hybrid messenger RNA transcripts from der14. The subsequent selection of activating mutations of the translocated FGFR3 by MM cells indicates an important role for this signaling pathway in tumor development and progression. To investigate the mechanism by which FGFR3 overexpression promotes MM development, interleukin-6 (IL-6)-dependent murine B9 cells were transduced with retroviruses expressing functional wild-type or constitutively activated mutant FGFR3. Overexpression of mutant FGFR3 resulted in IL-6 independence, decreased apoptosis, and an enhanced proliferative response to IL-6. In the presence of ligand, wild-type FGFR3-expressing cells also exhibited enhanced proliferation and survival in comparison to controls. B9 clones expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed increased phosphorylation of STAT3 and higher levels of bcl-xL expression than did parental B9 cells after cytokine withdrawal. The mechanism of the enhanced cell responsiveness to IL-6 is unknown at this time, but does not appear to be mediated by the mitogen-activated protein kinases SAPK, p38, or ERK. These findings provide a rational explanation for the mechanism by which FGFR3 contributes to both the viability and propagation of the myeloma clone and provide a basis for the development of therapies targeting this pathway.

scholarly journals A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1.

1991 ◽  
Vol 11 (10) ◽  
pp. 5068-5078 ◽  
Author(s):  
M Mohammadi ◽  
A M Honegger ◽  
D Rotin ◽  
R Fischer ◽  
F Bellot ◽  
...  
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Binding Site ◽  
Fibroblast Growth Factor ◽  
Tryptic Peptide ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Sh2 Domain ◽  
Fibroblast Growth ◽  
Wild Type

Phospholipase C-gamma (PLC-gamma) is a substrate of the fibroblast growth factor receptor (FGFR; encoded by the flg gene) and other receptors with tyrosine kinase activity. It has been demonstrated that the src homology region 2 (SH2 domain) of PLC-gamma and of other signalling molecules such as GTPase-activating protein and phosphatidylinositol 3-kinase-associated p85 direct their binding toward tyrosine-autophosphorylated regions of the epidermal growth factor or platelet-derived growth factor receptor. In this report, we describe the identification of Tyr-766 as an autophosphorylation site of flg-encoded FGFR by direct sequencing of a tyrosine-phosphorylated tryptic peptide isolated from the cytoplasmic domain of FGFR expressed in Escherichia coli. The same phosphopeptide was found in wild-type FGFR phosphorylated either in vitro or in living cells. Like other growth factor receptors, tyrosine-phosphorylated wild-type FGFR or its cytoplasmic domain becomes associated with intact PLC-gamma or with a fusion protein containing the SH2 domain of PLC-gamma. To delineate the site of association, we have examined the capacity of a 28-amino-acid tryptic peptide containing phosphorylated Tyr-766 to bind to various constructs containing SH2 and other domains of PLC-gamma. It is demonstrated that the tyrosine-phosphorylated peptide binds specifically to the SH2 domain but not to the SH3 domain or other regions of PLC-gamma. Hence, Tyr-766 and its flanking sequences represent a major binding site in FGFR for PLC-gamma. Alignment of the amino acid sequences surrounding Tyr-766 with corresponding regions of other FGFRs revealed conserved tyrosine residues in all known members of the FGFR family. We propose that homologous tyrosine-phosphorylated regions in other FGFRs also function as binding sites for PLC-gamma and therefore are involved in coupling to phosphatidylinositol breakdown.

scholarly journals Kinase Activity of Fibroblast Growth Factor Receptor 3 Regulates Activity of the Papillomavirus E2 Protein

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Fang Xie ◽  
Marsha DeSmet ◽  
Sriramana Kanginakudru ◽  
Leny Jose ◽  
Sara P. Culleton ◽  
...  
Keyword(s):  
Life Cycle ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Activity ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Mutant Form ◽  
Fibroblast Growth ◽  
E2 Protein ◽  
Viral Copy Number

ABSTRACT The papillomavirus (PV) E2 protein is a DNA binding, protein interaction platform that recruits viral and host factors necessary for transcription and replication. We recently discovered phosphorylation of a tyrosine (Y102) in bovine PV (BPV) E2. To identify the responsible factor, we tested several candidate tyrosine kinases that are highly expressed in keratinocytes for binding to BPV-1 E2. Fibroblast growth factor receptor 3 (FGFR3) coimmunoprecipitated with the BPV-1 E2 protein, as did human papillomavirus 31 (HPV-31) E2, which also colocalized with FGFR3 within the nucleus. A constitutively active mutant form of FGFR3 decreased BPV-1 and HPV-31 transient replication although this result also occurred in a BPV-1 E2 mutant lacking a previously identified phosphorylation site of interest (Y102). Furthermore, FGFR3 depletion in cell lines that maintain HPV-31 episomes increased viral copy number. These results suggest that FGFR3 kinase activity may regulate the PV reproductive program through phosphorylation of the E2 protein although this is unlikely to occur through the Y102 residue of HPV E2. IMPORTANCE The papillomavirus (PV) is a double-stranded DNA tumor virus infecting cervix, mouth, and throat tissues. The viral protein E2 is responsible for the replication of the virus. Understanding the mechanisms of the replicative life cycle of the virus may bring to light direct targets and treatments against viral infection. We recently found that the fibroblast growth factor receptor 3 (FGFR3) interacts with and mediates PV E2 function through phosphorylation of the E2 protein. Our study suggests that the function of the E2 protein may be regulated through a direct FGFR3 target during the maintenance stage of the PV life cycle.

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