Prickle is an evolutionarily conserved family of proteins exclusively associated with planar cell polarity (PCP) signalling. This signalling pathway provides directional and positional cues to eukaryotic cells along the plane of an epithelial sheet, orthogonal to both apicobasal and left-right axes. Through studies in the fruit fly Drosophila, we have learned that PCP signalling is manifested by the spatial segregation of two protein complexes, namely Prickle/Vangl and Frizzled/Dishevelled. While Vangl, Frizzled, and Dishevelled proteins have been extensively studied, Prickle has been largely neglected. This is likely because its role in vertebrate development and pathologies is still being explored and is not yet fully understood. The current review aims to address this gap by summarizing our current knowledge on vertebrate Prickle proteins and to cover their broad versatility. Accumulating evidence suggests that Prickle is involved in many developmental events, contributes to homeostasis, and can cause diseases when its expression and signalling properties are deregulated. This review highlights the importance of Prickle in vertebrate development, discusses the implications of Prickle-dependent signalling in pathology, and points out the blind spots or potential links regarding Prickle, which could be studied further.

• Klíčová slova
• Embryonic development, Pathology, Planar cell polarity (PCP), Prickle, Vertebrates,
• MeSH
• lidé MeSH
• obratlovci metabolismus   MeSH
• polarita buněk MeSH
• proteiny s doménou LIM * metabolismus   genetika   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• proteiny s doménou LIM * MeSH

The migratory properties of leukemic cells are commonly associated with their pathological potential and can significantly affect the disease progression. While the research in immunopathology mostly employed powerful indirect methods such as flow cytometry, these cells were rarely observed directly using live imaging microscopy. This is especially true for the malignant cells of the B-cell lineage, such as those originating from chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In this study, we employed open-source image analysis tools to automatically and quantitatively describe the amoeboid migration of four B-cell leukemic and lymphoma cell lines and primary CLL cells. To avoid the effect of the shear stress of the medium on these usually non-adherent cells, we have confined the cells using a modified under-agarose assay. Surprisingly, the behavior of tested cell lines differed substantially in terms of basal motility or response to chemokines and VCAM1 stimulation. Since casein kinase 1 (CK1) was reported as a regulator of B-cell migration and a promoter of CLL, we looked at the effects of CK1 inhibition in more detail. Migration analysis revealed that CK1 inhibition induced rapid negative effects on the migratory polarity of these cells, which was quantitatively and morphologically distinct from the effect of ROCK inhibition. We have set up an assay that visualizes endocytic vesicles in the uropod and facilitates morphological analysis. This assay hints that the effect of CK1 inhibition might be connected to defects in polarized intracellular transport. In summary, 1) we introduce and validate a pipeline for the imaging and quantitative assessment of the amoeboid migration of CLL/MCL cells, 2) we provide evidence that the assay is sensitive enough to mechanistically study migration defects identified by the transwell assay, and 3) we describe the polarity defects induced by inhibition or deletion of CK1ε.

• Klíčová slova
• B cells, amoeboid cell migration, casein kinase 1, chronic lymphocytic leukemia, live imaging, mantle cell lymphoma, uropod,
• Publikační typ
• časopisecké články MeSH

RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.

• Klíčová slova
• BRAF V600E, RNF43, ROR1, VANGL1, WNT5A, cancer biology, cell biology, human, melanoma, mouse,
• MeSH
• invazivní růst nádoru genetika   MeSH
• melanom * genetika   patologie   prevence a kontrola   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• protein Wnt 5a genetika   metabolismus   MeSH
• signální transdukce * MeSH
• ubikvitinligasy genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protein Wnt 5a MeSH
• RNF43 protein, human MeSH Prohlížeč
• ubikvitinligasy MeSH
• WNT5A protein, human MeSH Prohlížeč

The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.

• Klíčová slova
• AML, CK1α, CK1ε, CLL, MM, WNT pathway, casein kinase 1, inhibitors, leukemia, umbralisib,
• MeSH
• cílená molekulární terapie * MeSH
• hematologické nádory farmakoterapie   enzymologie   patologie   MeSH
• kaseinkinasa I antagonisté a inhibitory   chemie   metabolismus   MeSH
• lidé MeSH
• nádorové kmenové buňky účinky léků   metabolismus   patologie   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• signální dráha Wnt MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• kaseinkinasa I MeSH
• protinádorové látky MeSH

Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.

• MeSH
• analýza jednotlivých buněk metody   MeSH
• biosenzitivní techniky MeSH
• enzymatické testy metody   MeSH
• fluorescenční mikroskopie metody   MeSH
• fosforylace fyziologie   MeSH
• frizzled receptory metabolismus   MeSH
• genový knockout MeSH
• HEK293 buňky MeSH
• kaseinkinasa Iepsilon genetika   metabolismus   MeSH
• lidé MeSH
• mutageneze cílená MeSH
• oocyty MeSH
• PDZ domény fyziologie   MeSH
• protein dishevelled genetika   metabolismus   MeSH
• rezonanční přenos fluorescenční energie MeSH
• signální dráha Wnt fyziologie   MeSH
• simulace molekulární dynamiky MeSH
• Xenopus laevis MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DVL3 protein, human MeSH Prohlížeč
• frizzled receptory MeSH
• FZD6 protein, human MeSH Prohlížeč
• kaseinkinasa Iepsilon MeSH
• protein dishevelled MeSH

UNLABELLED: In this review, we discuss the intricate roles of the Wnt signalling network in the development and progression of mature B-cell-derived haematological malignancies, with a focus on chronic lymphocytic leukaemia (CLL) and related B-cell lymphomas. We review the current literature and highlight the differences between the β-catenin-dependent and -independent branches of Wnt signalling. Special attention is paid to the role of the non-canonical Wnt/planar cell polarity (PCP) pathway, mediated by the Wnt-5-receptor tyrosine kinase-like orphan receptor (ROR1)-Dishevelled signalling axis in CLL. This is mainly because the Wnt/PCP co-receptor ROR1 was found to be overexpressed in CLL and the Wnt/PCP pathway contributes to numerous aspects of CLL pathogenesis. We also discuss the possibilities of therapeutically targeting the Wnt signalling pathways as an approach to disrupt the crucial interaction between malignant cells and their micro-environment. We also advocate the need for research in this direction for other lymphomas, namely, diffuse large B-cell lymphoma, Hodgkin lymphoma, mantle cell lymphoma, Burkitt lymphoma and follicular lymphoma where the Wnt signalling pathway probably plays a similar role. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.

• MeSH
• B-buněčný lymfom diagnóza   metabolismus   MeSH
• chronická lymfatická leukemie diagnóza   metabolismus   MeSH
• lidé MeSH
• signální dráha Wnt * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Apico-basal polarity is typical of cells present in differentiated epithelium while front-rear polarity develops in motile cells. In cancer development, the transition from epithelial to migratory polarity may be seen as the hallmark of cancer progression to an invasive and metastatic disease. Despite the morphological and functional dissimilarity, both epithelial and migratory polarity are controlled by a common set of polarity complexes Par, Scribble and Crumbs, phosphoinositides, and small Rho GTPases Rac, Rho and Cdc42. In epithelial tissues, their mutual interplay ensures apico-basal and planar cell polarity. Accordingly, altered functions of these polarity determinants lead to disrupted cell-cell adhesions, cytoskeleton rearrangements and overall loss of epithelial homeostasis. Polarity proteins are further engaged in diverse interactions that promote the establishment of front-rear polarity, and they help cancer cells to adopt different invasion modes. Invading cancer cells can employ either the collective, mesenchymal or amoeboid invasion modes or actively switch between them and gain intermediate phenotypes. Elucidation of the role of polarity proteins during these invasion modes and the associated transitions is a necessary step towards understanding the complex problem of metastasis. In this review we summarize the current knowledge of the role of cell polarity signaling in the plasticity of cancer cell invasiveness.

• Klíčová slova
• AMT, EMT, invasion, plasticity, polarity,
• MeSH
• invazivní růst nádoru patologie   MeSH
• lidé MeSH
• nádory patologie   MeSH
• polarita buněk fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH