Synergistic Activation of the Wnt Signaling Pathway by Dvl and Casein Kinase Iε

Kishida, Michiko; Hino, Shinjiro; Michiue, Tatsuo; Yamamoto, Hideki; Kishida, Shosei; Fukui, Akimasa; Asashima, Makoto; Kikuchi, Akira

doi:10.1074/jbc.m103555200

Cited by 110 publications

(122 citation statements)

References 71 publications

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“…However, overexpressed CK1⑀ could be also found in association with all other mutants tested, with the exception of the extreme C terminus (mutant aa 496 -716). Our results confirm previous findings that map the binding domains of CK1 to the DEP domain or its close proximity (compare aa 332-716 and 496 -716 mutants and Kishida et al (19)) and to the basic region preceding the PDZ domain (see mutant aa 1-246 and Klein et al (33) and Klimowski et al (34)). Endogenous CK2␣ could be co-immunoprecipitated with all the mutants of Dvl3, which contained a basic region between the DIX and PDZ domains,.…”

Section: Csupporting

confidence: 82%

“…Wnt-induced activation of Dvl is visible as a Wnt-induced shift in the electrophoretic mobility of all three Dvl isoforms, forming the so called phosphorylated and shifted (PS) Dvl (14 -16). It has been clearly demonstrated that both the activation of Dvl in the Wnt/␤-catenin pathway (17)(18)(19)(20)(21) and Wnt-induced PS-Dvl formation are dependent on casein kinase 1 (CK1) ␦/⑀ activity (14,16). It is, thus, conceivable that CK1␦/⑀ phosphorylation of Dvl promotes the formation of signalosomes/Dvl aggregates, which is unique for the Wnt/␤-catenin pathway.…”

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confidence: 99%

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Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

Bernatík

Ganji

Dijksterhuis

et al. 2011

Journal of Biological Chemistry

101

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Section: Csupporting

confidence: 82%

mentioning

confidence: 99%

Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

Bernatík

Ganji

Dijksterhuis

et al. 2011

Journal of Biological Chemistry

101

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“…BRE-luc was from P. ten Dijke 28 . pCGN-Dvl-1 was described previously 29 . Soluble forms of LRP6 deletion mutants and probes for in situ hybridization analysis (Nkx2.5, cTnI and Hex) were generated by PCR.…”

Section: Methodsmentioning

confidence: 99%

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Zhu

Shiojima

Ito

et al. 2008

Nature

Self Cite

201

165

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Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs) 1 . Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown 1,2 . Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, lowdensity lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.The heart is the first organ to form during embryogenesis, and abnormalities in this process result in congenital heart diseases, the most common cause of birth defects in humans 3 . Molecules that mediate cardiogenesis are of particular interest because of their potential use for cardiac regeneration 4,5 . Previous studies have shown that soluble growth factors such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), Wnts and Wnt inhibitors mediate the tissue interactions that are crucial for cardiomyocyte specification 3,4 . We proposed that there might be additional soluble factors that modulate cardiac development and/or cardiomyocyte differentiation.P19CL6 cells differentiate into cardiomyocytes with high efficiency in the presence of 1% dimethylsulphoxide (DMSO) 6 . We cultured P19CL6 cells with culture media conditioned by various cell types in the absence of DMSO, and screened the cardiogenic activity of the conditioned media. The extent of cardiomyocyte differentiation was assessed by the immunostaining with MF20 monoclonal antibody that recognizes sarcomeric myosin heavy chain (MHC). Among the several cell types tested, culture media conditioned by a murine stromal cell line OP9 induced cardiomyocyte differentiation of P19CL6 cells without DMSO treatment (Fig. 1a, left and middle panels). Increased MF20-positive area was accompanied by the induction of cardiac marker genes such as aMHC, Nkx2.5 and GATA-4, and by the increased protein levels of cardiac troponin T (cTnT) (Fig. 1a, right panel). In contrast, culture media conditioned by COS7 cells, mouse embryonic fibroblasts, NIH3T3 cells, HeLa cells, END2 cells (visceral endoderm-like cells), neonatal rat cardiomyocytes and neonatal rat cardiac fibroblasts did not induce cardiomyocyte differentiation of P19CL6 cells in the absence of DMSO (Fig. 1a and data not shown). From these observations, we p...

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“…However, evidence exists that the DEP domain influences b-catenin signaling (Wong et al 2000;Simons et al 2009;Tauriello et al 2012). DVL associates with kinases such as CK11 and CK2, and becomes hyperphosphorylated upon Wnt signaling (Willert et al 1997;Peters et al 1999;Kishida et al 2001;Cong et al 2004a;Klein et al 2006). These kinases, in particular CK11, have been documented to have activating roles in Wnt/b-catenin signaling, but the role of DVL phosphorylation remains unclear.…”

Section: The Wnt -Fzd -Lrp5/6 Complexmentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

495

411

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Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

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Synergistic Activation of the Wnt Signaling Pathway by Dvl and Casein Kinase Iε

Cited by 110 publications

References 71 publications

Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

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