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Molecular Cancer Research
Molecular Cancer Research

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Cancer "-omics"

Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and β-Catenin–Independent Targets by Proteomics

Olesja Popow, João A. Paulo, Michael H. Tatham, Melanie S. Volk, Alejandro Rojas-Fernandez, Nicolas Loyer, Ian P. Newton, Jens Januschke, Kevin M. Haigis and Inke Näthke
Olesja Popow
Cancer Research Institute and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
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  • ORCID record for Olesja Popow
João A. Paulo
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
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Michael H. Tatham
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
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Melanie S. Volk
Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
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  • ORCID record for Melanie S. Volk
Alejandro Rojas-Fernandez
Center for Interdisciplinary Studies on the Nervous System (CISNe) and Institute of Medicine, Universidad Austral de Chile, Valdivia, Chile.
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Nicolas Loyer
Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
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Ian P. Newton
Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
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  • ORCID record for Ian P. Newton
Jens Januschke
Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
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Kevin M. Haigis
Cancer Research Institute and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.Harvard Digestive Disease Center, Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Kevin M. Haigis
Inke Näthke
Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
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  • ORCID record for Inke Näthke
  • For correspondence: I.s.nathke@dundee.ac.uk
DOI: 10.1158/1541-7786.MCR-18-1154 Published September 2019
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Abstract

Adenomatous Polyposis Coli (APC) is the most frequently mutated gene in colorectal cancer. APC negatively regulates the Wnt signaling pathway by promoting the degradation of β-catenin, but the extent to which APC exerts Wnt/β-catenin–independent tumor-suppressive activity is unclear. To identify interaction partners and β-catenin–independent targets of endogenous, full-length APC, we applied label-free and multiplexed tandem mass tag-based mass spectrometry. Affinity enrichment-mass spectrometry identified more than 150 previously unidentified APC interaction partners. Moreover, our global proteomic analysis revealed that roughly half of the protein expression changes that occur in response to APC loss are independent of β-catenin. Combining these two analyses, we identified Misshapen-like kinase 1 (MINK1) as a putative substrate of an APC-containing destruction complex. We validated the interaction between endogenous MINK1 and APC and further confirmed the negative, and β-catenin–independent, regulation of MINK1 by APC. Increased Mink1/Msn levels were also observed in mouse intestinal tissue and Drosophila follicular cells expressing mutant Apc/APC when compared with wild-type tissue/cells. Collectively, our results highlight the extent and importance of Wnt-independent APC functions in epithelial biology and disease.

Implications: The tumor-suppressive function of APC, the most frequently mutated gene in colorectal cancer, is mainly attributed to its role in β-catenin/Wnt signaling. Our study substantially expands the list of APC interaction partners and reveals that approximately half of the changes in the cellular proteome induced by loss of APC function are mediated by β-catenin–independent mechanisms.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2019;17:1828–41

  • Received October 26, 2018.
  • Revision received April 11, 2019.
  • Accepted May 28, 2019.
  • Published first June 3, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 17 (9)
September 2019
Volume 17, Issue 9
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Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and β-Catenin–Independent Targets by Proteomics
Olesja Popow, João A. Paulo, Michael H. Tatham, Melanie S. Volk, Alejandro Rojas-Fernandez, Nicolas Loyer, Ian P. Newton, Jens Januschke, Kevin M. Haigis and Inke Näthke
Mol Cancer Res September 1 2019 (17) (9) 1828-1841; DOI: 10.1158/1541-7786.MCR-18-1154

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Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and β-Catenin–Independent Targets by Proteomics
Olesja Popow, João A. Paulo, Michael H. Tatham, Melanie S. Volk, Alejandro Rojas-Fernandez, Nicolas Loyer, Ian P. Newton, Jens Januschke, Kevin M. Haigis and Inke Näthke
Mol Cancer Res September 1 2019 (17) (9) 1828-1841; DOI: 10.1158/1541-7786.MCR-18-1154
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