Michaela BosakovaMasaryk University | MUNI · Department of Biology
Michaela Bosakova
PhD
About
59
Publications
9,803
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Introduction
Michaela is trying to understand how protein kinases function in cells.
Additional affiliations
May 2022 - present
Institute of Animal Physiology and Genetics CAS, v. v. i.
Position
- Principal Investigator
January 2020 - April 2022
Masaryk University
Position
- Research Scientist
January 2020 - April 2022
Education
May 2018 - December 2019
ICRC - St. Ann's University Hospital Brno
Field of study
- Cilia kinases
May 2015 - April 2018
October 2014 - April 2015
Cancer Research Institute
Field of study
- FGFR signaling
Publications
Publications (59)
The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in...
Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for signif...
Significance
A properly functioning primary cilium is prerequisite for both normal development and aging of all ciliated organisms, including humans. In vertebrates, the signaling of Hedgehog family morphogens depends entirely on primary cilium. Recently, we reported that fibroblast growth factors (FGF) signaling interacts with that of Hedgehog, an...
Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional prima...
Achondroplasia is the most prevalent genetic form of dwarfism in humans and is caused by activating mutations in FGFR3 tyrosine kinase. The clinical need for a safe and effective inhibitor of FGFR3 is unmet, leaving achondroplasia currently incurable. Here, we evaluated RBM-007, an RNA aptamer previously developed to neutralize the FGFR3 ligand FGF...
Alterations in the balance between skeletogenesis and adipogenesis is a pathogenic feature in multiple skeletal disorders. Clinically, enhanced bone marrow adiposity in bones impairs mobility and increases fracture risk, reducing the quality of life of patients. The molecular mechanism that underlies the balance between skeletogenesis and adipogene...
Discontinuation of the tyrosine kinase inhibitor (TKI) therapy leads to relapse in chronic myeloid leukemia (CML), suggesting that TKIs do not completely eliminate cancer cells. Recently, we showed that TKIs inhibit catalytic activity of BCR-ABL, but do not dissolve the BCR-ABL core complex, consisting of signaling mediators SHC1, GRB2, SOS1, cCBL,...
Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degenera...
Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex function of FGFR3 in growing skeleton were characterized, which facilitated identification of therapy targets, and drove progress toward treatment. In August 2021, the vosoritide was...
Primary cilia are dynamic compartments that regulate multiple aspects of cellular signaling. The production, maintenance, and function of cilia involve more than 1000 genes in mammals, and their mutations disrupt the ciliary signaling which manifests in a plethora of pathological conditions—the ciliopathies. Skeletal ciliopathies are genetic disord...
The Sprouty family is a highly conserved group of intracellular modulators of receptor tyrosine kinase (RTK)‐signaling pathways, which have been recently linked to primary cilia. Disruptions in the structure and function of primary cilia cause inherited disorders called ciliopathies. We aimed to evaluate Sprouty2 and Sprouty4 gene dependent alterat...
A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogen...
Background
Beyond its structural role in the skeleton, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skele...
Many patients with chronic myeloid leukemia in deep remission experience return of clinical disease after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR–ABL, which allows the survival of cancer cells, and relapse. We show that TKI treatment inhibits catalytic activity of BCR–ABL, but does not dissolve BCR–A...
Approximately 50% of chronic myeloid leukemia (CML) patients in deep remission experience a return of clinical CML after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR-ABL, which allows for survival of cancer cells, leading to relapse. Understanding the dynamics of BCR-ABL signaling complex holds a key to t...
Background
Approximately 50% of chronic myeloid leukemia (CML) patients in deep remission experience a return of clinical CML after withdrawal of tyrosine kinase inhibitors (TKIs), suggesting signaling of catalytically inactive BCR‐ABL. This allows for survival of cancer cells responsible for CML relapse after discontinuation of the TKI therapy. El...
Cylindrospermopsin (CYN) has been recognized as a potent waterborne hepatotoxin with an increasing environmental occurrence. However, CYN effects on the specific populations of hepatic cells involved in liver tissue development, renewal and regeneration, have not been characterized yet. We used human embryonic stem cells to analyze the hepatic diff...
Sustained activation of extracellular signal–regulated kinase (ERK) drives pathologies caused by mutations in fibroblast growth factor receptors (FGFRs). We previously identified the inositol phosphatase SHIP2 (also known as INPPL1) as an FGFR-interacting protein and a target of the tyrosine kinase activities of FGFR1, FGFR3, and FGFR4. We report t...
Yersiniosis belongs to the common foodborne diseases around the world, and frequently manifests as diarrhea that can be treated with probiotics. Colicin FY is an antibacterial agent produced by bacteria and it is capable of specific growth inhibition of Yersinia enterocolitica, the causative agent of gastrointestinal yersiniosis. In this study, rec...
The blocking of specific protein-protein interactions using nanoparticles is an emerging alternative to small molecule-based therapeutic interventions. However, the nanoparticles designed as "artificial proteins" generally require modification of their surface with (bio)organic molecules and/or polymers to ensure their selectivity and specificity o...
The cover image, by Pavel Dvorak et al., is based on the Article Computer-assisted engineering of hyperstable fibroblast growth factor 2, DOI 10.1002/bit.26531.
Fibroblast growth factors (FGFs) serve numerous regulatory functions in complex organisms, and their corresponding therapeutic potential is of growing interest to academics and industrial researchers alike. However, applications of these proteins are limited due to their low stability. Here we tackle this problem using a generalizable computer-assi...
Many tyrosine kinase inhibitors (TKIs) have failed to reach human use due to insufficient activity in clinical trials. However, the failed TKIs may still benefit patients if their other kinase targets are identified by providing treatment focused on syndromes driven by these kinases. Here, we searched for novel targets of AZD1480, an inhibitor of J...
Receptor tyrosine kinases (RTKs) form multiprotein complexes that initiate and propagate intracellular signals and determine the RTK-specific signalling patterns. Unravelling the full complexity of protein interactions within the RTK-associated complexes is essential for understanding of RTK functions, yet it remains an understudied area of cell bi...
Human embryonic stem cells (hESCs) represent promising tool to study functions of genes during development, to model diseases, and to even develop therapies when combined with gene editing techniques such as CRISPR/Cas9 system. However, the process of disruption of gene expression by generation of null alleles is often inefficient and tedious. To c...
Tyrosine kinase inhibitors are being developed for therapy of malignancies caused by oncogenic FGFR signaling but little is known about their effect in congenital chondrodysplasias or craniosynostoses that associate with activating FGFR mutations. Here, we investigated the effects of novel FGFR inhibitor, ARQ 087, in experimental models of aberrant...
Human pluripotent stem cells (hPSC) require signaling provided by fibroblast growth factor (FGF) receptors. This can be initiated by the recombinant FGF2 ligand supplied exogenously, but hPSC further support their niche by secretion of endogenous FGF2. In this study, we describe a role of TEC kinase (tyrosine kinase expressed in hepatocellular carc...
Primary cilium is a solitary organelle that emanates from the surface of most postmitotic mammalian cells and serves as a sensory organelle, transmitting the mechanical and chemical cues to the cell. Primary cilia are key coordinators of various signaling pathways during development and maintenance of tissue homeostasis. The emerging evidence impli...
Objective: Statins are widely used drugs for cholesterol lowering, which were recently found to counteract the effects of aberrant FGFR3 signaling in cell and animal models of FGFR3-related chondrodysplasia. This opened an intriguing therapeutic possibility for human dwarfing conditions caused by gain-of-function mutations in FGFR3, although the me...
Supplementary tables containing
(A) Commercial providers of RTK activity profiling; (B) Nucleotide sequences cloned into the promoterless pGL4.17 vector expressing firefly luciferase; (C) Expression vectors used in the study; (D) Antibodies used in the study; (E) Literature survey of anti-RTK activity of BCR-ABL TKIs; (F) Primers used for reporter...
Supplementary file contains numerical data for Figure 1A,B,C,D and E; Figure 1—figure supplements 3, 4, 5A, B, 7A and B; and Figure 5—figure supplement 1.
DOI:
http://dx.doi.org/10.7554/eLife.21536.018
Supplementary file contains numerical data for Figure 5B.
DOI:
http://dx.doi.org/10.7554/eLife.21536.019
In-cell profiling enables the evaluation of receptor tyrosine activity in a complex environment of regulatory networks that affect signal initiation, propagation and feedback. We used FGF-receptor signaling to identify EGR1 as a locus that strongly responds to the activation of a majority of the recognized protein kinase oncogenes, including 30 rec...
Fibroblast growth factors (FGFs) play numerous regulatory functions in complex organisms, and their corresponding therapeutic potential is of growing interest to academics and industrial researchers alike. However, applications of these proteins are limited due to their low stability in vivo and in vitro . Here we tackle this problem using a genera...
HMGB1 and HMGB2 proteins have been implicated in numerous cellular processes, including proliferation, differentiation, apoptosis, and tumor growth. It is unknown whether they are involved in regulating the typical functions of pluripotent human embryonic stem cells (hESCs) and/or those of the differentiated derivatives of hESCs. Using inducible, s...
The fibroblast growth factor receptors (FGFRs) are important oncogenes promoting tumor progression in many types of cancer, such as breast, bladder, and lung cancer as well as multiple myeloma and rhabdomyosarcoma. However, little is known about how these receptors are internalized and down-regulated in cells. We have here applied proximity biotin...
MORN5 (MORN repeat containing 5) is encoded by a locus positioned on chromosome 17 in the chicken genome. The MORN motif is found in multiple copies in several proteins including junctophilins or phosphatidylinositol phosphate kinase family and the MORN proteins themselves are found across the animal and plant kingdoms. MORN5 protein has a characte...
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism,
achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating
ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kina...
The successional dental lamina (SDL) plays an essential role in the development of replacement teeth in diphyodont and polyphyodont animals. A morphologically similar structure, the rudimental successional dental lamina (RSDL), has been described in monophyodont (only one tooth generation) lizards on the lingual side of the developing functional to...
The generation of human pluripotent stem cells (hPSCs) of sufficient quantity and quality remains a major challenge for biomedical application. Here we present an efficient feeder-free, high-density monolayer system in which hPSCs become SSEA-3-high and gradually more viable than their feeder-dependent counterparts without changes attributed to cul...
For human embryonic stem cells (ESC) to be used in cell replacement therapies, they must be grown under good manufacturing conditions in a chemically defined medium that lacks animal proteins. This study examined the ability of a newly designed medium containing the plant-derived serum replacement VegetaCell and other reagents of human origin to su...
The transcription program that is responsible for the pluripotency of human ESCs (hESCs) is believed to be comaintained by exogenous fibroblast growth factor-2 (FGF-2), which activates FGF receptors (FGFRs) and stimulates the mitogen-activated protein kinase (MAPK) pathway. However, the same pathway is stimulated by insulin receptors, insulin-like...