Human type A Enteroviruses (EV-As) cause diseases ranging from hand-foot-and-mouth disease to poliomyelitis-like disease. Although cellular receptors are identified for some EV-As, they remain ...elusive for the majority of EV-As. We identify the cell surface molecule KREMEN1 as an entry receptor for coxsackievirus A10 (CV-A10). Whereas loss of KREMEN1 renders cells resistant to CV-A10 infection, KREMEN1 overexpression enhances CV-A10 binding to the cell surface and increases susceptibility to infection, indicating that KREMEN1 is a rate-limiting factor for CV-A10 infection. Furthermore, the extracellular domain of KREMEN1 binds CV-A10 and functions as a neutralizing agent during infection. Kremen-deficient mice are resistant to CV-A10-induced lethal paralysis, emphasizing the relevance of Kremen for infection in vivo. KREMEN1 is also essential for infection by a phylogenetic and pathogenic related group of EV-As. Collectively these findings highlight the importance of KREMEN1 for these emerging pathogens and its potential as an antiviral therapeutic target.
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•Haploid genetic screen identifies KREMEN1 as a host factor for coxsackievirus A10•KREMEN deficiency protects mice from coxsackievirus A10 infection•KREMEN1 binds to virus particles and acts as an entry receptor•KREMEN1 functions as receptor for additional human type A Enteroviruses
Staring et al. identify KREMEN1 as host factor for coxsackievirus A10 (CV-A10) using a genetic screen in haploid human cells. KREMEN1 binds to viral particles and acts as virus receptor for CV-A10 and additional members of the Enterovirus type A species.
Dickkopf (Dkk) genes comprise an evolutionary conserved small gene family of four members (Dkk1-4) and a unique Dkk3-related gene, Dkkl1 (soggy). They encode secreted proteins that typically ...antagonize Wnt/beta-catenin signaling, by inhibiting the Wnt coreceptors Lrp5 and 6. Additionally, Dkks are high affinity ligands for the transmembrane proteins Kremen1 and 2, which also modulate Wnt signaling. Dkks play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer's disease.
Istarski poluotok bogat je mineralnim sirovinama, ponajprije karbonatnim i silicijskim sedimentnim stijenama koje su na ovom području neraskidivo povezane procesom koji se naziva silicifikacija. ...Silicijske sedimentne stijene (rožnjaci) zbog svoje su tvrdoće i školjkastog loma vrlo pogodne za izradu oruđa lomljenjem ili cijepanjem, stoga je znanje o ležištima ove vrste stijena bilo vrlo važno za prapovijesne zajednice u Istri. U ovom radu iznijet ćemo osnovne podatke o primarnim i sekundarnim ležištima rožnjaka na području hrvatskog dijela Istarskog poluotoka, vizualne i mehaničke karakteristike sakupljenih uzoraka, kao i mikropetrografske karakteristike određene pomoću binokularnog polarizacijskog mikroskopa. Iznijet ćemo podatke o geološkoj starosti stijene domaćina u kojima su zabilježeni rožnjaci. Spomenut ćemo terminološku problematiku u arheološkoj literaturi te postaviti pitanje istraživanja provenijencije istarskog rožnjaka, odnosno mogućnost raspoznavanja sirovine s različitih ležišta na poluotoku. Spomenut ćemo i arheološka nalazišta na kojima je zabilježena prisutnost istarske sirovine. Na nekim ležištima rožnjaka pronađene su i izrađevine, odnosno jezgre koje su služile za proizvodnju odbojaka ili sječiva, a koje su također dokumentirane.
The Istrian Peninsula is rich in mineral resources, primarily carbonate and siliceous sedimentary rocks, which are inextricably linked by a process called silicification. Due to their hardness and conchoidal fracture, siliceous sedimentary rocks (cherts) are very suitable for knapping tools, therefore the knowledge about the location of chert deposits was very important for prehistoric communities in Istria. In this paper, we will present basic data on primary and secondary chert deposits in the Croatian part of the Istrian Peninsula, visual and mechanical characteristics of the collected samples, as well as micropetrographic characteristics determined using a binocular polarizing microscope. We will present data on the geological age of the host rock in which cherts were recorded. We will mention the terminological issues in the archaeological literature and raise the issue of research into the provenance of Istrian chert, that is, the possibility of identifying the raw material from different deposits on the Peninsula. We will also mention the archaeological sites where the presence of Istrian raw materials was recorded. Artifacts and cores used to knap flakes and blades were also found and recorded on some of the surveyed chert deposits.
The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/β-catenin signaling pathway. We have previously shown that RSpo proteins can induce proliferative effects on the ...gastrointestinal epithelium in mice. Here we provide a mechanism whereby RSpo1 regulates cellular responsiveness to Wnt ligands by modulating the cell-surface levels of the coreceptor LRP6. We show that RSpo1 activity critically depends on the presence of canonical Wnt ligands and LRP6. Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface. Our results support a model in which RSpo1 relieves the inhibition DKK1 imposes on the Wnt pathway.
Wnt signaling regulates essential biological processes ranging from embryogenesis to neurodegeneration. Recently, we demonstrated that Dickkopf3 (Dkk3) is a pro-survival glycoprotein that positively ...modulates Wnt signaling. An important step in understanding the mechanism of action of Dkk3 is identifying its interacting proteins in the Wnt pathway. In this study, we used a series of biochemical and functional assays to investigate the interaction between Dkk3 and the Wnt pathway receptors Kremen1 (Krm1), Kremen 2 (Krm2) and low-density lipoprotein receptor-related protein 6 (LRP6). Here, we report that, contrary to previous studies, Dkk3 interacts with Krm1 and Krm2. However, Dkk3 did not interact with, or alter expression of, LRP6. Blocking protein glycosylation did not alter the interaction between Dkk3 and Krm proteins. Additionally, Krm2 abolished Dkk3-mediated potentiation of Wnt signaling. Therefore, our data establish that Krm proteins are novel binding partners of Dkk3 and suggest a mechanism by which Dkk3 potentiates Wnt signaling.
The article is dedicated to the 70th anniversary of Vasyl Hryhorovych Kremen, Doctor of Philosophy, Academician of the National Academy of Sciences of Ukraine and the National Academy of Pedagogical ...Sciences of Ukraine, a prominent Ukrainian scholar, statesman and science manager. It highlights his main achievements and his great contribution to the development of Ukrainian education, and the development of Vasyl Stefanyk Precarpathian National University, where he was awarded Honorary Doctor’s Degree.
Kremen 1 and 2 (Krm1/2) are transmembrane receptors for Wnt antagonists of the Dickkopf (Dkk) family and function by inhibiting the Wnt co-receptors LRP5/6. Here we show that Krm2 functions ...independently from Dkks during neural crest (NC) induction in Xenopus. Krm2 is co-expressed with, and regulated by, canonical Wnts. Krm2 is differentially expressed in the NC, and morpholino-mediated Krm2 knockdown inhibits NC induction, which is mimicked by LRP6 depletion. Conversely, krm2 overexpression induces ectopic NC. Kremens bind to LRP6, promote its cell-surface localization and stimulate LRP6 signaling. Furthermore, Krm2 knockdown specifically reduces LRP6 protein levels in NC explants. The results indicate that in the absence of Dkks, Kremens activate Wnt/beta-catenin signaling through LRP6.
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Introduction
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Identification and structure of Krm
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Krm as a negative regulator in Wnt signalling
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Expression of Krm
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Krm in development
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Wnt signalling in stem cell regulation and ...diseases
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Wnt signalling, Krm and cancer
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Perspectives
Kremen (Krm) was originally discovered as a novel transmembrane protein containing the kringle domain. Both Krm1 (the first identified Krm) and its relative Krm2 were later identified to be the high‐affinity receptors for Dickkopf (Dkk), the inhibitor of Wnt/β‐catenin signalling. The formation of a ternary complex composed of Krm, Dkk, and Lrp5/6 (the coreceptor of Wnt) inhibits Wnt/β‐catenin signalling. In Xenopus gastrula embryos, Wnt/β‐catenin signalling regulates anterior‐posterior patterning, with low‐signalling in anterior regions. Inhibition of Krm1/2 induces embryonic head defects. Together with anterior localization of Krms and Dkks, the inhibition of Wnt signalling by Dkk‐Krm action seems to allow anterior embryonic development. During mammalian development, krm1 mRNA expression is low in the early stages, but gradually and continuously increases with developmental progression and differentiation. In contrast with the wide, strong expression of krm1 mRNA in mature tissues, expression of krm1 is diminished in a variety of human tumor cells. Since stem cells and undifferentiated cells rely on Wnt/β‐catenin signalling for maintenance in a low differentiation state, the physiological shutdown of Wnt/β‐catenin signalling by Dkk‐Krm is likely to set cells on a divergent path toward differentiation. In tumour cells, a deficit of Krm may increase the susceptibility to tumourigenic transformation. Both positive and negative regulation of Wnt/β‐catenin signalling definitively contributes to diverse developmental and physiological processes, including cell‐fate determination, tissue patterning and stem cell regulation. Krm is quite significant in these processes as the gatekeeper of the Wnt/β‐catenin signalling pathway.
A gradient of Wnt/beta-catenin signalling formed by posteriorising Wnts and anteriorising Wnt antagonists regulates anteroposterior (AP) patterning of the central nervous system (CNS) during Xenopus ...gastrulation. In this process, the secreted Wnt antagonist Dkk1 functions in the Spemann organiser and its anterior derivatives by blocking Wnt receptors of the lipoprotein receptor-related protein (LRP) 5 and 6 class. In addition to LRP6, Dkk1 interacts with another recently identified receptor class, the transmembrane proteins Kremen1 (Krm1) and Kremen2 (Krm2) to synergistically inhibit LRP6. We have investigated the role of Krm1 and Krm2 during early Xenopus embryogenesis. Consistent with a role in zygotic Wnt inhibition, overexpressed Krm anteriorises embryos and rescues embryos posteriorised by Wnt8. Antisense morpholino oligonucleotide (Mo) knockdown of Krm1 and Krm2 leads to deficiency of anterior neural development. In this process, Krm proteins functionally interact with Dkk1: (1) in axis duplication assays krm2 synergises with dkk1 in inhibiting Wnt/LRP6 signalling; (2) krm2 rescues microcephalic embryos induced by injection of inhibitory anti-Dkk1 antibodies; and (3) injection of krm1/2 antisense Mo enhances microcephaly induced by inhibitory anti-Dkk1 antibodies. The results indicate that Krm proteins function in a Wnt inhibition pathway regulating early AP patterning of the CNS.
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