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Article ; Online: An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy.

Bernkopf, Dominic B / Brückner, Martina / Hadjihannas, Michel V / Behrens, Jürgen

2019 Volume 10, Issue 1, Page(s) 4251

Abstract: The paralogous scaffold proteins axin and conductin/axin2 are key factors in the negative regulation of the Wnt pathway transcription factor β-catenin, thereby representing interesting targets for signaling regulation. Polymerization of axin proteins is ... ...

Abstract	The paralogous scaffold proteins axin and conductin/axin2 are key factors in the negative regulation of the Wnt pathway transcription factor β-catenin, thereby representing interesting targets for signaling regulation. Polymerization of axin proteins is essential for their activity in suppressing Wnt/β-catenin signaling. Notably, conductin shows less polymerization and lower activity than axin. By domain swapping between axin and conductin we here identify an aggregation site in the conductin RGS domain which prevents conductin polymerization. Induction of conductin polymerization by point mutations of this aggregon results in enhanced inhibition of Wnt/β-catenin signaling. Importantly, we identify a short peptide which induces conductin polymerization via masking the aggregon, thereby enhancing β-catenin degradation, inhibiting β-catenin-dependent transcription and repressing growth of colorectal cancer cells. Our study reveals a mechanism for regulating signaling pathways via the polymerization status of scaffold proteins and suggests a strategy for targeted colorectal cancer therapy.
MeSH term(s)	Axin Protein/genetics ; Axin Protein/metabolism ; CRISPR-Cas Systems/genetics ; Cell Line, Tumor ; Cell Proliferation ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Gene Knockout Techniques ; HEK293 Cells ; Humans ; Wnt Proteins/metabolism ; Wnt Signaling Pathway/genetics ; Wnt Signaling Pathway/physiology ; beta Catenin/metabolism
Chemical Substances	AXIN2 protein, human ; Axin Protein ; CTNNB1 protein, human ; Wnt Proteins ; beta Catenin
Language	English
Publishing date	2019-09-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-12203-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy

Dominic B. Bernkopf / Martina Brückner / Michel V. Hadjihannas / Jürgen Behrens

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 14

Abstract: Polymerization of axin proteins is essential to suppress Wnt/β-catenin signaling. Here, the authors identify an aggregation site in the conductin/axin2 RGS domain that prevents its polymerization and show that a short peptide masking this aggregon ... ...

Abstract	Polymerization of axin proteins is essential to suppress Wnt/β-catenin signaling. Here, the authors identify an aggregation site in the conductin/axin2 RGS domain that prevents its polymerization and show that a short peptide masking this aggregon promotes polymerization of conductin/axin2, downregulation of Wnt pathway activity and growth inhibition of colorectal cancer cells.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy

Dominic B. Bernkopf / Martina Brückner / Michel V. Hadjihannas / Jürgen Behrens

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 14

Abstract	Polymerization of axin proteins is essential to suppress Wnt/β-catenin signaling. Here, the authors identify an aggregation site in the conductin/axin2 RGS domain that prevents its polymerization and show that a short peptide masking this aggregon promotes polymerization of conductin/axin2, downregulation of Wnt pathway activity and growth inhibition of colorectal cancer cells.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Negative-feedback regulation of the Wnt pathway by conductin/axin2 involves insensitivity to upstream signalling.

Bernkopf, Dominic B / Hadjihannas, Michel V / Behrens, Jürgen

Journal of cell science

2015 Volume 128, Issue 1, Page(s) 33–39

Abstract: Axin and conductin (also known as axin2) are structurally related inhibitors of Wnt/β-catenin signalling that promote degradation of β-catenin. Whereas axin is constitutively expressed, conductin is a Wnt target gene implicated in Wnt negative-feedback ... ...

Abstract	Axin and conductin (also known as axin2) are structurally related inhibitors of Wnt/β-catenin signalling that promote degradation of β-catenin. Whereas axin is constitutively expressed, conductin is a Wnt target gene implicated in Wnt negative-feedback regulation. Here, we show that axin and conductin differ in their functional interaction with the upstream Wnt pathway component Dvl. Conductin shows reduced binding to Dvl2 compared to axin, and degradation of β-catenin by conductin is only poorly blocked by Dvl2. We propose that insensitivity to Dvl is an important feature of the role of conductin as a negative-feedback regulator of Wnt signalling.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Axin Protein/genetics ; Axin Protein/metabolism ; Dishevelled Proteins ; HEK293 Cells ; Humans ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Wnt Signaling Pathway/physiology
Chemical Substances	AXIN2 protein, human ; Adaptor Proteins, Signal Transducing ; Axin Protein ; DVL2 protein, human ; Dishevelled Proteins ; Phosphoproteins
Language	English
Publishing date	2015-01-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.159145
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Book ; Online ; Thesis: The role of the Wnt-b-catenin [Wnt-beta-catenin] target gene conductin in mitosis and chromosomal instability of colorectal cancer

Hadjihannas, Michel V

2007

Author's details	vorgelegt von Michel V. Hadjihannas
Language	English
Size	Online-Ressource
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Nürnberg, Univ., Diss--Erlangen, 2006
Database	Former special subject collection: coastal and deep sea fishing

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Book ; Online ; Thesis: The role of the Wnt-β-catenin [Wnt-beta-catenin] target gene conductin in mitosis and chromosomal instability of colorectal cancer

Hadjihannas, Michel V. [Verfasser]

2007

Author's details	vorgelegt von Michel V. Hadjihannas
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	English
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: CIN By WNT: growth pathways, mitotic control and chromosomal instability in cancer.

Hadjihannas, Michel V / Behrens, Jürgen

Cell cycle (Georgetown, Tex.)

2006 Volume 5, Issue 18, Page(s) 2077–2081

Abstract: There is mounting evidence suggesting that an instable genome is directly involved in the development of cancer. The predominant form of genomic instability in most cancers presents itself as an increased rate of loss or gain in chromosome number and ... ...

Abstract	There is mounting evidence suggesting that an instable genome is directly involved in the development of cancer. The predominant form of genomic instability in most cancers presents itself as an increased rate of loss or gain in chromosome number and parts, referred to as chromosomal instability (CIN). Indeed, mutations in components of mitotic checkpoints have been described in human cancers, albeit in low numbers, suggesting that although CIN principally arises due to defective surveillance of mitosis, its molecular causes remain largely unclear. We have recently shown that the Wnt/beta-catenin signaling pathway, whose aberrant activation has been established as the driving force of tumorigenesis in many cancers particularly colorectal cancer, can generate CIN through the transcriptional target gene conductin/axin2. Here we propose a model for the generation of CIN by aberrant Wnt/beta-catenin signaling and we suggest that growth pathways not only control cell cycle progression through G(1)/S transition but have also evolved cross talks to regulate mitosis. We speculate that aberrant activation of these pathways, as observed in cancer can result in chromosomal instability thus explaining the widespread appearance of CIN in human cancers.
MeSH term(s)	Animals ; Axin Protein ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Chromosomal Instability/genetics ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; Genes, cdc/physiology ; Humans ; Mitosis/genetics ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/physiopathology ; Signal Transduction/genetics ; Wnt Proteins/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics ; beta Catenin/metabolism
Chemical Substances	AXIN2 protein, human ; Axin Protein ; Cytoskeletal Proteins ; Wnt Proteins ; beta Catenin
Language	English
Publishing date	2006-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.5.18.3282
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Conductin/axin2 and Wnt signalling regulates centrosome cohesion.

Hadjihannas, Michel V / Brückner, Martina / Behrens, Jürgen

EMBO reports

2010 Volume 11, Issue 4, Page(s) 317–324

Abstract: Activated Wnt/beta-catenin signalling is a characteristic of many cancers and drives cell-cycle progression. Here, we report a mechanism linking Wnt/beta-catenin signalling to centrosome separation. We show that conductin/axin2, a negative regulator of ... ...

Abstract	Activated Wnt/beta-catenin signalling is a characteristic of many cancers and drives cell-cycle progression. Here, we report a mechanism linking Wnt/beta-catenin signalling to centrosome separation. We show that conductin/axin2, a negative regulator of beta-catenin, localizes at the centrosomes by binding to the centriole-associated component C-Nap1. Knockout or knockdown of conductin leads to premature centrosome separation--that is, splitting--which is abolished by knockdown of beta-catenin. Conductin promotes phosphorylation of the amino-terminal serine (Ser 33/37) and threonine (Thr 41) residues of centrosome-associated beta-catenin. Beta-catenin mutated at these residues causes centrosomal splitting, whereas a phospho-mimicking mutant of beta-catenin does not. Importantly, beta-catenin-induced splitting is not inhibited by blocking beta-catenin-dependent transcription. Treatment with Wnts and inhibition of glycogen synthase kinase 3 block beta-catenin phosphorylation and induce centrosomal splitting. These data indicate that Wnt/beta-catenin signalling and conductin regulate centrosomal cohesion by altering the phosphorylation status of beta-catenin at the centrosomes.
MeSH term(s)	Autoantigens/metabolism ; Axin Protein ; Blotting, Western ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Centrosome/metabolism ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; Humans ; Microscopy, Fluorescence ; Models, Biological ; Phosphorylation/genetics ; Phosphorylation/physiology ; Signal Transduction/genetics ; Signal Transduction/physiology ; Tubulin/metabolism ; Wnt Proteins/metabolism ; beta Catenin/metabolism
Chemical Substances	AXIN2 protein, human ; Autoantigens ; Axin Protein ; Cell Cycle Proteins ; CEP250 protein, human ; Cytoskeletal Proteins ; Tubulin ; Wnt Proteins ; beta Catenin
Language	English
Publishing date	2010-03-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.1038/embor.2010.23
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Zs.A 5433: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Cell cycle control of Wnt/β-catenin signalling by conductin/axin2 through CDC20.

Hadjihannas, Michel V / Bernkopf, Dominic B / Brückner, Martina / Behrens, Jürgen

EMBO reports

2011 Volume 13, Issue 4, Page(s) 347–354

Abstract: Wnt/β-catenin signalling regulates cell proliferation by modulating the cell cycle and is negatively regulated by conductin/axin2/axil. We show that conductin levels peak at G2/M followed by a rapid decline during return to G1. In line with this, Wnt/β- ... ...

Abstract	Wnt/β-catenin signalling regulates cell proliferation by modulating the cell cycle and is negatively regulated by conductin/axin2/axil. We show that conductin levels peak at G2/M followed by a rapid decline during return to G1. In line with this, Wnt/β-catenin target genes are low at G2/M and high at G1/S, and β-catenin phosphorylation oscillates during the cell cycle in a conductin-dependent manner. Conductin is degraded by the anaphase-promoting complex/cyclosome cofactor CDC20. Knockdown of CDC20 blocks Wnt signalling through conductin. CDC20-resistant conductin inhibits Wnt signalling and attenuates colony formation of colorectal cancer cells. We propose that CDC20-mediated degradation of conductin regulates Wnt/β-catenin signalling for maximal activity during G1/S.
MeSH term(s)	Amino Acid Sequence ; Animals ; Axin Protein/chemistry ; Axin Protein/metabolism ; Cdc20 Proteins ; Cell Cycle Checkpoints ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Conserved Sequence ; Humans ; Mice ; Mitosis ; Molecular Sequence Data ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Protein Stability ; Protein Structure, Tertiary ; Proteolysis ; Rats ; Wnt Signaling Pathway ; beta Catenin/metabolism
Chemical Substances	AXIN2 protein, human ; Axin Protein ; Cdc20 Proteins ; Cell Cycle Proteins ; beta Catenin ; CDC20 protein, human (156288-95-8) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2011-11-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.1038/embor.2012.12
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Article ; Online: Chromatin-Remodeling-Factor ARID1B Represses Wnt/β-Catenin Signaling.

Vasileiou, Georgia / Ekici, Arif B / Uebe, Steffen / Zweier, Christiane / Hoyer, Juliane / Engels, Hartmut / Behrens, Jürgen / Reis, André / Hadjihannas, Michel V

American journal of human genetics

2015 Volume 97, Issue 3, Page(s) 445–456

Abstract: The link of chromatin remodeling to both neurodevelopment and cancer has recently been highlighted by the identification of mutations affecting BAF chromatin-remodeling components, such as ARID1B, in individuals with intellectual disability and cancer. ... ...

Abstract	The link of chromatin remodeling to both neurodevelopment and cancer has recently been highlighted by the identification of mutations affecting BAF chromatin-remodeling components, such as ARID1B, in individuals with intellectual disability and cancer. However, the underlying molecular mechanism(s) remains unknown. Here, we show that ARID1B is a repressor of Wnt/β-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/β-catenin target genes are upregulated. Using cellular models of low and high Wnt/β-catenin activity, we demonstrate that knockdown of ARID1B activates Wnt/β-catenin target genes and Wnt/β-catenin-dependent transcriptional reporters in a β-catenin-dependent manner. Reciprocally, forced expression of ARID1B inhibits Wnt/β-catenin signaling downstream of the β-catenin destruction complex. Both endogenous and exogenous ARID1B associate with β-catenin and repress Wnt/β-catenin-mediated transcription through the BAF core subunit BRG1. Accordingly, mutations in ARID1B leading to partial or complete deletion of its BRG1-binding domain, as is often observed in intellectual disability and cancers, compromise association with β-catenin, and the resultant ARID1B mutant proteins fail to suppress Wnt/β-catenin signaling. Finally, knockdown of ARID1B in mouse neuroblastoma cells leads to neurite outgrowth through β-catenin. The data suggest that aberrations in chromatin-remodeling factors, such as ARID1B, might contribute to neurodevelopmental abnormalities and cancer through deregulation of developmental and oncogenic pathways, such as the Wnt/β-catenin signaling pathway.
MeSH term(s)	Blotting, Western ; Chromatin Assembly and Disassembly/genetics ; Computational Biology ; DNA, Complementary/biosynthesis ; DNA-Binding Proteins/genetics ; Humans ; Immunoprecipitation ; Luciferases ; Microscopy, Fluorescence ; RNA, Small Interfering/genetics ; Real-Time Polymerase Chain Reaction ; Transcription Factors/genetics ; Wnt Signaling Pathway/genetics ; beta Catenin/metabolism
Chemical Substances	ARID1B protein, human ; DNA, Complementary ; DNA-Binding Proteins ; RNA, Small Interfering ; Transcription Factors ; beta Catenin ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2015-09-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2015.08.002
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