The mammalian intestine is one of the most rapidly self-renewing tissues, driven by stem cells residing at the crypt bottom. Paneth cells form a major element of the niche microenvironment providing various growth factors to orchestrate intestinal stem cell homeostasis, such as Wnt3. Different Wnt ligands can selectively activate β-catenin-dependent (canonical) or -independent (noncanonical) signaling. Here, we report that the Dishevelled-associated activator of morphogenesis 1 (Daam1) and its paralogue Daam2 asymmetrically regulate canonical and noncanonical Wnt (Wnt/PCP) signaling. Daam1/2 interacts with the Wnt inhibitor RNF43, and Daam1/2 double knockout stimulates canonical Wnt signaling by preventing RNF43-dependent degradation of the Wnt receptor, Frizzled (Fzd). Single-cell RNA sequencing analysis revealed that Paneth cell differentiation is impaired by Daam1/2 depletion because of defective Wnt/PCP signaling. Together, we identified Daam1/2 as an unexpected hub molecule coordinating both canonical and noncanonical Wnt, which is fundamental for specifying an adequate number of Paneth cells.

• MeSH
• buněčná diferenciace MeSH
• kmenové buňky metabolismus   MeSH
• Panethovy buňky * MeSH
• savci MeSH
• signální dráha Wnt * MeSH
• střeva MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• 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

UNLABELLED: This themed section of the British Journal of Pharmacology stems from the EMBO Conference: Wnt Meeting 2016 held from the 14th to 16th September 2016 in Brno, Czech Republic. 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
• buněčná membrána účinky léků   metabolismus   MeSH
• lidé MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky farmakologie   MeSH
• signální dráha Wnt účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• úvodní články MeSH
• úvodníky MeSH
• Názvy látek
• protinádorové látky MeSH