Projects per year
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.
|Number of pages||14|
|Journal||Molecular Cancer Research|
|Early online date||3 Jun 2019|
|Publication status||Published - Sept 2019|
- Adenomatous polyposis coli
- destruction complex
- colorectal cancer
- Misshapen-like kinase 1
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
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- 7 Finished
Molecular and Cellular Biology 4 Year PhD Studentship
Hay, R. & Ryan, R.
5/09/16 → 4/09/20
Development of Live Tissue Imaging Capabilities Using Multiphoton Confocal Microscopy
Muller, A., Nathke, I., Storey, K. & Weijer, K.
30/06/14 → 29/06/19
Sonopill: Minimally Invasive Gastrointestinal Diagnosis and Therapy (Joint with University of Glasgow & Heriot Watt University)
Cochran, S., Corner, G., Cuschieri, A., Nathke, I. & Steele, B.
Engineering and Physical Sciences Research Council
27/05/13 → 14/12/18