scholarly journals Lacrimo-Auriculo-Dento-Digital Syndrome Is Caused by Reduced Activity of the Fibroblast Growth Factor 10 (FGF10)-FGF Receptor 2 Signaling Pathway

2007 ◽  
Vol 27 (19) ◽  
pp. 6903-6912 ◽  
Author(s):  
Imad Shams ◽  
Edyta Rohmann ◽  
Veraragavan P. Eswarakumar ◽  
Erin D. Lew ◽  
Satoru Yuzawa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Biological Activities ◽  
Fibroblast Growth ◽  
Loss Of Function ◽  
Fgf Receptor ◽  
Fibroblast Growth Factor 10 ◽  
Ladd Syndrome

ABSTRACT Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by abnormalities in lacrimal and salivary glands, in teeth, and in the distal limbs. Genetic studies have implicated heterozygous mutations in fibroblast growth factor 10 (FGF10) and in FGF receptor 2 (FGFR2) in LADD syndrome. However, it is not clear whether LADD syndrome mutations (LADD mutations) are gain- or loss-of-function mutations. In order to reveal the molecular mechanism underlying LADD syndrome, we have compared the biological properties of FGF10 LADD and FGFR2 LADD mutants to the activities of their normal counterparts. These experiments show that the biological activities of three different FGF10 LADD mutants are severely impaired by different mechanisms. Moreover, haploinsufficiency caused by defective FGF10 mutants leads to LADD syndrome. We also demonstrate that the tyrosine kinase activities of FGFR2 LADD mutants expressed in transfected cells are strongly compromised. Since tyrosine kinase activity is stimulated by ligand-induced receptor dimerization, FGFR2 LADD mutants may also exert a dominant inhibitory effect on signaling via wild-type FGFR2 expressed in the same cell. These experiments underscore the importance of signal strength in mediating biological responses and that relatively small changes in receptor signaling may influence the outcome of developmental processes in cells or organs that do not possess redundant signaling pathway.

Colonic atresia without mesenteric vascular occlusion. The role of the fibroblast growth factor 10 signaling pathway

2005 ◽  
Vol 40 (2) ◽  
pp. 390-396 ◽  
Author(s):  
Timothy J. Fairbanks ◽  
Robert C. Kanard ◽  
Pierre M. Del Moral ◽  
Fred G. Sala ◽  
Stijn P. De Langhe ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Vascular Occlusion ◽  
Fibroblast Growth ◽  
Mesenteric Vascular Occlusion ◽  
Colonic Atresia ◽  
Fibroblast Growth Factor 10

scholarly journals A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway

2019 ◽  
Vol 8 (4) ◽  
pp. 500 ◽  
Author(s):  
Ernesto Martín-Núñez ◽  
Javier Donate-Correa ◽  
Caroline Kannengiesser ◽  
David-Paul De Brauwere ◽  
Christine Leroy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Mononuclear Cells ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Loss Of Function ◽  
Heterozygous Deletion ◽  
Phosphate Homeostasis ◽  
Exon 2

Hyperphosphatemia is commonly present in end-stage renal disease. Klotho (KL) is implicated in phosphate homeostasis since it acts as obligate co-receptor for the fibroblast growth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variation in the KL gene might be associated with alterations in phosphate homeostasis resulting in hyperphosphatemia. We performed sequencing for determining KL gene variants in a group of resistant hyperphosphatemic dialysis patients. In a 67-year-old female, blood DNA sequencing revealed a heterozygous deletion of a T at position 1041 (c.1041delT) in exon 2. This variation caused a frameshift with substitution of isoleucine for phenylalanine and introduction of a premature termination codon (p.Ile348Phefs*28). cDNA sequencing showed absence of deletion-carrier transcripts in peripheral blood mononuclear cells suggesting degradation of these through a nonsense-mediated RNA decay pathway. Experiments in vitro showed that p.Ile348Phefs*28 variant impaired FGF23 signaling pathway, indicating a functional inactivation of the gene. In the patient, serum levels of KL were 2.9-fold lower than the mean level of a group of matched dialysis subjects, suggesting a compromise in the circulating protein concentration due to haploinsufficiency. These findings provide a new loss-of-function variant in the human KL gene, suggesting that genetic determinants might be associated to clinical resistant hyperphosphatemia.

scholarly journals Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets

2021 ◽  
Vol 12 ◽  
Author(s):  
Haijun Wang ◽  
Jie Yang ◽  
Ke Zhang ◽  
Jia Liu ◽  
Yushan Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Biological Activities ◽  
Primary Liver Cancer ◽  
Genetic Alterations ◽  
Research Progress ◽  
Fibroblast Growth ◽  
Incidence And Mortality

Hepatocellular carcinoma (HCC) is a type of primary liver cancer with poor prognosis, and its incidence and mortality rate are increasing worldwide. It is refractory to conventional chemotherapy and radiotherapy owing to its high tumor heterogeneity. Accumulated genetic alterations and aberrant cell signaling pathway have been characterized in HCC. The fibroblast growth factor (FGF) family and their receptors (FGFRs) are involved in diverse biological activities, including embryonic development, proliferation, differentiation, survival, angiogenesis, and migration, etc. Data mining results of The Cancer Genome Atlas demonstrate high levels of FGF and/or FGFR expression in HCC tumors compared with normal tissues. Moreover, substantial evidence indicates that the FGF/FGFR signaling axis plays an important role in various mechanisms that contribute to HCC development. At present, several inhibitors targeting FGF/FGFR, such as multikinase inhibitors, specific FGFR4 inhibitors, and FGF ligand traps, exhibit antitumor activity in preclinical or early development phases in HCC. In this review, we summarize the research progress regarding the molecular implications of FGF/FGFR-mediated signaling and the development of FGFR-targeted therapeutics in hepatocarcinogenesis.

Sign in / Sign up

Export Citation Format

Share Document