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MUC13 interaction with receptor tyrosine kinase HER2 drives pancreatic ductal adenocarcinoma progression

Oncogene volume 36, pages 491–500 (2017)Cite this article

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Abstract

Although MUC13, a transmembrane mucin, is aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC) and generally correlates with increased expression of HER2, the underlying mechanism remains poorly understood. Herein, we found that MUC13 co-localizes and interacts with HER2 in PDAC cells (reciprocal co-immunoprecipitation, immunofluorescence, proximity ligation, co-capping assays) and tissues (immunohistofluorescence). The results from this study demonstrate that MUC13 functionally interacts and activates HER2 at p1248 in PDAC cells, leading to stimulation of HER2 signaling cascade, including ERK1/2, FAK, AKT and PAK1 as well as regulation of the growth, cytoskeleton remodeling and motility, invasion of PDAC cells—all collectively contributing to PDAC progression. Interestingly, all of these phenotypic effects of MUC13–HER2 co-localization could be effectively compromised by depleting MUC13 and mediated by the first and second EGF-like domains of MUC13. Further, MUC13–HER2 co-localization also holds true in PDAC tissues with a strong functional correlation with events contributing to increased degree of disorder and cancer aggressiveness. In brief, findings presented here provide compelling evidence of a functional ramification of MUC13–HER2: this interaction could be potentially exploited for targeted therapeutics in a subset of patients harboring an aggressive form of PDAC.

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Acknowledgements

This work was partially supported by grants from the National Institutes of Health (R01 CA142736 to SCC, U01 CA162106A to SCC and MJ; R01 EB003682 to PP; K22CA174841 to MMY), the Department of Defense (PC130870 to SCC and MJ), the College of Pharmacy 2014 and 2015 Dean's Seed/Instrument Grants of the University of Tennessee Health Science Center (to SCC, MJ and MMY) and Grants of the University of Memphis (to PP). We acknowledge the Herb Kosten Foundation for pancreatic cancer research support (UT 14-0558 to SCC). We are also thankful to Cathy Christopherson for editorial assistance.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA

    S Khan, M Sikander, A Ganju, S Kumari, M M Yallapu, B B Hafeez, S C Chauhan & M Jaggi

  2. Cancer Biology Research Center, Sanford Research, , Sioux Falls, SD, USA

    M C Ebeling

  3. Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki City, Osaka, Japan

    T Ise & S Nagata

  4. Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA

    N Zafar

  5. Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA

    S W Behrman

  6. Department of Biostatistics & Epidemiology, University of Tennessee Health Science Center, Memphis, TN, USA

    J Y Wan

  7. Department of Physics, University of Memphis, Memphis, TN, USA

    H M Ghimire, P Sahay & P Pradhan

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  1. S Khan
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  2. M Sikander
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  9. S Nagata
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Correspondence to S C Chauhan or M Jaggi.

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Khan, S., Sikander, M., Ebeling, M. et al. MUC13 interaction with receptor tyrosine kinase HER2 drives pancreatic ductal adenocarcinoma progression. Oncogene 36, 491–500 (2017). https://doi.org/10.1038/onc.2016.218

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  • DOI: https://doi.org/10.1038/onc.2016.218

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