Wnt Signaling in Vertebrate Axis Specification

Hikasa, Hiroki; Sokol, Sergei Y.

doi:10.1101/cshperspect.a007955

Cited by 154 publications

(160 citation statements)

References 290 publications

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“…During development, Wnt regulates stem cell differentiation, embryonic patterning and organogenesis [1][2][3]. Wnt also regulates adult tissue homeostasis, and dysregulation of this pathway often leads to diseases such as cancer, in which Wnt signaling is frequently hyperactivated [1,4].…”

Section: Introduction -Wnt Signalingmentioning

confidence: 99%

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Ploper

Robertis

2015

Pharmacological Research

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a b s t r a c tCanonical Wnt signaling influences cellular fate and proliferation through inhibition of Glycogen Synthase Kinase (GSK3) and the subsequent stabilization of its many substrates, most notably ␤-Catenin, a transcriptional co-activator. MITF, a melanoma oncogene member of the microphthalmia family of transcription factors (MiT), was recently found to contain novel GSK3 phosphorylation sites and to be stabilized by Wnt. Other MiT members, TFEB and TFE3, are known to play important roles in cellular clearance pathways by transcriptionally regulating the biogenesis of lysosomes and autophagosomes via activation of CLEAR elements in gene promoters of target genes. Recent studies suggest that MITF can also upregulate many lysosomal genes. MiT family members are dysregulated in cancer and are considered oncogenes, but the underlying oncogenic mechanisms remain unclear. Here we review the role of MiT members, including MITF, in lysosomal biogenesis, and how cancers overexpressing MITF, TFEB or TFE3 could rewire the lysosomal pathway, inhibit cellular senescence, and activate Wnt signaling by increasing sequestration of negative regulators of Wnt signaling in multivesicular bodies (MVBs). Microarray studies suggest that MITF expression inhibits macroautophagy. In melanoma the MITF-driven increase in MVBs generates a positive feedback loop between MITF, Wnt, and MVBs.

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Section: Introduction -Wnt Signalingmentioning

confidence: 99%

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Ploper

Robertis

2015

Pharmacological Research

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“…During development, Wnt signaling regulates cell fate decisions that influence a myriad of developmental events as diverse as establishment of the vertebrate axis, control of bone development, and the wiring of the neural circuitry (Cadigan and Peifer 2009;Regard et al 2012;Salinas 2012;Hikasa and Sokol 2013). Wnt signaling continues to be critical in adult homeostasis, as it is involved in the maintenance of certain mammalian stem cells (Holland et al 2013).…”

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confidence: 99%

Testing Models of the APC Tumor Suppressor/β-Catenin Interaction Reshapes Our View of the Destruction Complex in Wnt Signaling

Yamulla¹,

Kane²,

Moody³

et al. 2014

Genetics

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The Wnt pathway is a conserved signal transduction pathway that contributes to normal development and adult homeostasis, but is also misregulated in human diseases such as cancer. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling inactivated in .80% of colorectal cancers. APC participates in a multiprotein "destruction complex" that targets the proto-oncogene b-catenin for ubiquitin-mediated proteolysis; however, the mechanistic role of APC in the destruction complex remains unknown. Several models of APC function have recently been proposed, many of which have emphasized the importance of phosphorylation of high-affinity b-catenin-binding sites [20-amino-acid repeats (20Rs)] on APC. Here we test these models by generating a Drosophila APC2 mutant lacking all b-catenin-binding 20Rs and performing functional studies in human colon cancer cell lines and Drosophila embryos. Our results are inconsistent with current models, as we find that b-catenin binding to the 20Rs of APC is not required for destruction complex activity. In addition, we generate an APC2 mutant lacking all b-catenin-binding sites (including the 15Rs) and find that a direct b-catenin/APC interaction is also not essential for b-catenin destruction, although it increases destruction complex efficiency in certain developmental contexts. Overall, our findings support a model whereby b-catenin-binding sites on APC do not provide a critical mechanistic function per se, but rather dock b-catenin in the destruction complex to increase the efficiency of b-catenin destruction. Furthermore, in Drosophila embryos expressing some APC2 mutant transgenes we observe a separation of b-catenin destruction and Wg/Wnt signaling outputs and suggest that cytoplasmic retention of b-catenin likely accounts for this difference.

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“…Wnt signaling | centrosome | Dishevelled | NEK2 | linker proteins S ignaling pathways activated by Wnt ligands are evolutionary conserved drivers of proliferation, differentiation, and morphogenesis (1). Their deregulation leads to numerous developmental abnormalities and contributes to the pathogenesis of several cancers (2).…”

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confidence: 99%

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

Červenka

Valnohová

Bernatík

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dishevelled (DVL) is a key scaffolding protein and a branching point in Wnt signaling pathways. Here, we present conclusive evidence that DVL regulates the centrosomal cycle. We demonstrate that DVL dishevelled and axin (DIX) domain, but not DIX domain-mediated multimerization, is essential for DVL's centrosomal localization. DVL accumulates during the cell cycle and associates with NIMA-related kinase 2 (NEK2), which is able to phosphorylate DVL at a multitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunitassociated protein 2 (CDK5RAP2) and centrosomal Nek2-associated protein 1 (C-NAP1), two proteins of the centrosomal linker. Displacement of DVL from the centrosome and its release into the cytoplasm on NEK2 phosphorylation is coupled to the removal of linker proteins, an event necessary for centrosomal separation and proper formation of the mitotic spindle. Lack of DVL prevents NEK2-controlled dissolution of loose centrosomal linker and subsequent centrosomal separation. Increased DVL levels, in contrast, sequester centrosomal NEK2 and mimic monopolar spindle defects induced by a dominant negative version of this kinase. Our study thus uncovers molecular crosstalk between centrosome and Wnt signaling.Wnt signaling | centrosome | Dishevelled | NEK2 | linker proteins

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Wnt Signaling in Vertebrate Axis Specification

Cited by 154 publications

References 290 publications

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Testing Models of the APC Tumor Suppressor/β-Catenin Interaction Reshapes Our View of the Destruction Complex in Wnt Signaling

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

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