A5026718940- Fibroblast Growth Factor Research
- Connective tissue disorders research
- Proteoglycans and glycosaminoglycans research
- Epigenetics and DNA Methylation
- Wnt/β-catenin signaling in development and cancer
- PI3K/AKT/mTOR signaling in cancer
- Protein Tyrosine Phosphatases
- Cancer-related gene regulation
- Chronic Lymphocytic Leukemia Research
- Hedgehog Signaling Pathway Studies
- Genetic and Kidney Cyst Diseases
- Kruppel-like factors research
- Chronic Myeloid Leukemia Treatments
- Galectins and Cancer Biology
- Pancreatic function and diabetes
- Cytokine Signaling Pathways and Interactions
- Bone fractures and treatments
- Genetic Syndromes and Imprinting
- Mast cells and histamine
- NF-κB Signaling Pathways
- Cell Adhesion Molecules Research
- Gene Regulatory Network Analysis
- Renal and related cancers
- Peptidase Inhibition and Analysis
- Hippo pathway signaling and YAP/TAZ
Masaryk University
2016-2025
University Hospital Brno
2015-2025
Institute of Animal Physiology of the Slovak Academy of Sciences
2023-2025
Czech Academy of Sciences, Institute of Animal Physiology and Genetics
2018-2025
St. Anne's University Hospital Brno
2016-2025
Goethe University Frankfurt
2023
Johns Hopkins University
2023
Institute of Nanotechnology
2023
Goethe Institut
2023
International Clinical Research Center, St. Anne's University Hospital Brno
2020
Receptor tyrosine kinase signaling cooperates with WNT/β-catenin in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation WNT co-receptor LRP6 at Ser1490 Thr1572 during its Golgi network-based maturation process. This dramatically increases cellular response to...
Activating mutations in FGFR3 cause achondroplasia and thanatophoric dysplasia, the most common human skeletal dysplasias. In these disorders, spinal canal foramen magnum stenosis can serious neurologic complications. Here, we provide evidence that MAPK signaling chondrocytes promote synchondrosis closure fusion of ossification centers. We observed premature spine cranial base cases homozygous dysplasia as well mouse models achondroplasia. both species, was associated with increased bone...
Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in fibroblast growth factor receptor-3 gene. Genetic overexpression C-type natriuretic peptide (CNP), a positive regulator endochondral bone growth, prevents dwarfism mouse models ACH. However, administration exogenous CNP compromised its rapid clearance vivo through receptor-mediated and proteolytic pathways. Using vitro approaches, we developed modified variants CNP,...
Overexpression of C-natriuretic peptide (CNP) in cartilage partially rescues achondroplasia the mouse. Here, we studied interaction fibroblast growth factor (FGF) and CNP signaling chondrocytes. antagonized FGF2-induced arrest rat chondrosarcoma (RCS) chondrocytes by inhibition Erk mitogen activated protein kinase pathway. This effect was G-dependent mimicked cGMP analog pCPT-cGMP. FGF2-mediated activation both MEK Raf-1 but not Ras or FRS2 abolished demonstrating that blocks pathway at...
LDL-related protein 6 (LRP6) is a coreceptor of WNTs and key regulator the WNT/-catenin pathway.Upon activation, LRP6 phosphorylated within its intracellular PPPS/TP motifs.These motifs are required to recruit axin inhibit glycogen synthase kinase 3 (GSK3), two basic components -catenin destruction complex.On basis kinome-wide small interfering RNA (siRNA) screen confirmative biochemical analysis, we show that several proline-directed mitogen-activated kinases (MAPKs), such as p38, ERK1/2,...
Dishevelled (Dvl) is a key component in the Wnt/β-catenin signaling pathway. Dvl can multimerize to form dynamic protein aggregates, which are required for activation of downstream signaling. Upon pathway by Wnts, becomes phosphorylated yield and shifted (PS) Dvl. Both Wnt-induced PS-Dvl formation dependent on casein kinase 1 (CK1) δ/ε activity. However, overexpression CK1 was shown dissolve endogenous forms irrespective whether or not activating Wnt triggers Using combination...
Abstract The planar cell polarity (PCP) pathway is a conserved that regulates migration and in various contexts. Here we show key PCP components such as Vangl2, Celsr1, Prickle1, FZD3, FZD7, Dvl2, Dvl3, casein kinase 1 (CK1)-ϵ are upregulated B lymphocytes of patients with chronic lymphocytic leukemia (CLL). Elevated levels proteins accumulate advanced stages the disease. Here, required for transendothelial invasion CLL cells high expression genes, PRICKLE1, have less favorable clinical...
Fibroblast growth factors (FGFs) serve numerous regulatory functions in complex organisms, and their corresponding therapeutic potential is of growing interest to academics industrial researchers alike. However, applications these proteins are limited due low stability. Here we tackle this problem using a generalizable computer-assisted protein engineering strategy create unique modified FGF2 with nine mutations displaying unprecedented stability uncompromised biological function. The data...
Lysine hydroxylation of type I collagen telopeptides varies from tissue to tissue, and these distinct patterns modulate cross-linking generate a unique extracellular matrix. Abnormalities in contribute pathologies that include osteogenesis imperfecta (OI), fibrosis, cancer. Telopeptide procollagen modifications are carried out by lysyl hydroxylase 2 (LH2); however, little is known regarding how this enzyme regulates patterns. We identified an ER complex resident chaperones includes HSP47,...
The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences FGFR1c response FGF4, FGF8, and FGF9, process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation extracellular matrix loss, while FGF4 FGF9 induce cell arrest. Thus, demonstrate biased...
Dishevelled (Dvl) is a multifunctional effector of different Wnt cascades. Both canonical Wnt3a and noncanonical Wnt5a stimulate casein-kinase-1 (CK1) -mediated phosphorylation Dvl, visualized as electrophoretic mobility shift [phosphorylated shifted Dvl (ps-Dvl)]. However, the role this remains obscure. Here we report functional interaction ps-Dvl with receptor tyrosine kinase Ror2, which an alternative able to inhibit signaling. We demonstrate between Ror2 at cell membrane after or...
Breast cancer is one of the most common types in women. One genes that were found mutated breast casein kinase 1 epsilon (CK1ε). Because CK1ε a crucial regulator Wnt signaling cascades, we determined how these mutations interfere with pathway and affect behavior epithelial cell lines. We performed silico modeling various analyzed activity mutants both vitro vivo. Furthermore, used reporter small GTPase assays to identify mutation affects different branches pathway. Based on results, employed...
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) their against signaling chondrocytes. All TKIs strongly inhibited activation cultured chondrocytes limb rudiment...
Osteogenesis imperfecta (OI) is a genetic disorder that results in low bone mineral density and brittle bones. Most cases result from dominant mutations the type I procollagen genes, but growing number of genes have been identified produce autosomal recessive forms disease. Among these include SERPINH1 FKBP10, which encode chaperones HSP47 FKBP65, respectively, predominantly moderately severe form OI. Little known about biochemical consequences how they We new OI mutation destabilization...
The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by ribs, shortened long bones, varying types and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing role for development. To identify additional SRPS discover novel ciliary molecules required normal skeletogenesis, we performed exome sequencing cohort patients identified homozygosity missense...
Disrupting the PTH/PTHrP-SIK3 pathway impairs degradation of DEPTOR, affects mTOR signaling, and leads to abnormalities in skeletal development.
We report reversal of the FGFR3-related skeletal dysplasia by RNA aptamer designed to neutralize FGFR3 ligand FGF2.