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TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression

Abstract

Epidermal growth factor receptor (EGFR) family members play pivotal roles in cell proliferation, differentiation and survival. Overexpression and mutations of EGFRs, or aberrant EGFR signaling are commonly associated with the development of various cancers, where constitutive NF-κB activation is often found to promote the expression of various proteins involved in the proliferation, survival, migration and epithelial-to-mesenchymal transition of cancer cells. However, the mechanism of EGFR-induced NF-κB activation is not fully defined. Here, we used a Bimolecular Fluorescence Complementation-based functional genomics method to perform a high throughput screening and identified TMEM43/LUMA as a critical component in EGFR signaling network, mediating EGFR-induced NF-κB activation. Our data show that EGFR recruits TMEM43 following EGF stimulation. TMEM43 interacts with the scaffold protein CARMA3 and its associating complex to induce downstream NF-κB activation, and plays a critical role in controlling cell survival. TMEM43 deficiency significantly affects colony formation, survival of anoikis-induced cell death, migration and invasion of cancer cells in vitro, as well as tumor progression in vivo. Importantly, higher expression of TMEM43 closely correlates with brain tumor malignancy, and suppression of TMEM43 expression in brain tumor cells inhibited their growth both in vitro and in vivo. Altogether, our studies reveal a crucial link of EGF receptor to NF-κB activation and tumor progression.

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References

  1. Biswas DK, Iglehart JD . Linkage between EGFR family receptors and nuclear factor kappaB (NF-kappaB) signaling in breast cancer. J Cell Physiol 2006; 209: 645–652.

    Article  CAS  Google Scholar 

  2. Biswas DK, Cruz AP, Gansberger E, Pardee AB . Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci USA 2000; 97: 8542–8547.

    Article  CAS  Google Scholar 

  3. Hayden MS, Ghosh S . Shared principles in NF-kappaB signaling. Cell 2008; 132: 344–362.

    Article  CAS  Google Scholar 

  4. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639–16647.

    Article  CAS  Google Scholar 

  5. Biswas DK, Martin KJ, McAlister C, Cruz AP, Graner E, Dai SC et al. Apoptosis caused by chemotherapeutic inhibition of nuclear factor-kappaB activation. Cancer Res 2003; 63: 290–295.

    CAS  PubMed  Google Scholar 

  6. Biswas DK, Singh S, Shi Q, Pardee AB, Iglehart JD . Crossroads of estrogen receptor and NF-kappaB signaling. Sci STKE 2005; 2005: pe27.

    PubMed  Google Scholar 

  7. Wang Z, Sengupta R, Banerjee S, Li Y, Zhang Y, Rahman KM et al. Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer. Cancer Res 2006; 66: 7653–7660.

    Article  CAS  Google Scholar 

  8. Ando K, Ohmori T, Inoue F, Kadofuku T, Hosaka T, Ishida H et al. Enhancement of sensitivity to tumor necrosis factor alpha in non-small cell lung cancer cells with acquired resistance to gefitinib. Clin Cancer Res 2005; 11: 8872–8879.

    Article  CAS  Google Scholar 

  9. Le Page C, Koumakpayi IH, Lessard L, Mes-Masson AM, Saad F . EGFR and Her-2 regulate the constitutive activation of NF-kappaB in PC-3 prostate cancer cells. Prostate 2005; 65: 130–140.

    Article  CAS  Google Scholar 

  10. Shimizu M, Deguchi A, Lim JT, Moriwaki H, Kopelovich L, Weinstein IB . (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin Cancer Res 2005; 11: 2735–2746.

    Article  CAS  Google Scholar 

  11. Marciniak DJ, Rishi AK, Sarkar FH, Majumdar AP . Epidermal growth factor receptor-related peptide inhibits growth of PC-3 prostate cancer cells. Mol Cancer Therap 2004; 3: 1615–1621.

    CAS  Google Scholar 

  12. Wang H, Wang H, Zhang W, Huang HJ, Liao WS, Fuller GN . Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Investig J Tech Methods Pathol 2004; 84: 941–951.

    Article  CAS  Google Scholar 

  13. Thornburg NJ, Pathmanathan R, Raab-Traub N . Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma. Cancer Res 2003; 63: 8293–8301.

    CAS  PubMed  Google Scholar 

  14. Bancroft CC, Chen Z, Yeh J, Sunwoo JB, Yeh NT, Jackson S et al. Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer 2002; 99: 538–548.

    Article  CAS  Google Scholar 

  15. Bhat-Nakshatri P, Sweeney CJ, Nakshatri H . Identification of signal transduction pathways involved in constitutive NF-kappaB activation in breast cancer cells. Oncogene 2002; 21: 2066–2078.

    Article  CAS  Google Scholar 

  16. Pianetti S, Arsura M, Romieu-Mourez R, Coffey RJ, Sonenshein GE . Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN. Oncogene 2001; 20: 1287–1299.

    Article  CAS  Google Scholar 

  17. Hayden MS, Ghosh S . Signaling to NF-kappaB. Genes Dev 2004; 18: 2195–2224.

    Article  CAS  Google Scholar 

  18. Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 2000; 18: 621–663.

    Article  CAS  Google Scholar 

  19. Blonska M, Lin X . NF-kappaB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res 2011; 21: 55–70.

    Article  CAS  Google Scholar 

  20. Grabiner BC, Blonska M, Lin P-C, You Y, Wang D, Sun J et al. CARMA3 deficiency abrogrates G-protein-coupled receptor-induced NF-kappaB activation. Genes Dev 2007; 21: 984–996.

    Article  CAS  Google Scholar 

  21. Jiang T, Grabiner B, Zhu Y, Jiang C, Li H, You Y et al. CARMA3 is crucial for EGFR-induced activation of NF-{kappa}B and tumor progression. Cancer Res 2011; 71: 2183–2192.

    Article  CAS  Google Scholar 

  22. Pan D, Jiang C, Ma Z, Blonska M, You MJ, Lin X . MALT1 is required for EGFR-induced NF-kappaB activation and contributes to EGFR-driven lung cancer progression. Oncogene 2015; 35: 919–928.

    Article  Google Scholar 

  23. Pan D, Zhu Y, Zhou Z, Wang T, You H, Jiang C et al. The CBM complex underwrites NF-kappaB activation to promote HER2-associated tumor malignancy. Mol Cancer Res 2016; 14: 93–102.

    Article  CAS  Google Scholar 

  24. Hu CD, Chinenov Y, Kerppola TK . Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol Cell 2002; 9: 789–798.

    Article  CAS  Google Scholar 

  25. Kerppola TK . Visualization of molecular interactions using bimolecular fluorescence complementation analysis: characteristics of protein fragment complementation. Chem Soc Rev 2009; 38: 2876–2886.

    Article  CAS  Google Scholar 

  26. Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet 2008; 82: 809–821.

    Article  CAS  Google Scholar 

  27. Bengtsson L, Otto H . LUMA interacts with emerin and influences its distribution at the inner nuclear membrane. J Cell Sci 2008; 121: 536–548.

    Article  CAS  Google Scholar 

  28. Dreger M, Bengtsson L, Schoneberg T, Otto H, Hucho F . Nuclear envelope proteomics: novel integral membrane proteins of the inner nuclear membrane. Proc Natl Acad Sci USA 2001; 98: 11943–11948.

    Article  CAS  Google Scholar 

  29. Vanderschuren KL, Sieverink T, Wilders R . Arrhythmogenic right ventricular dysplasia/cardiomyopathy type 1: a light on molecular mechanisms. Genet Res Int 2013; 2013: 460805.

    PubMed  PubMed Central  Google Scholar 

  30. Driskell OJ, Mironov A, Allan VJ, Woodman PG . Dynein is required for receptor sorting and the morphogenesis of early endosomes. Nat Cell Biol 2007; 9: 113–120.

    Article  CAS  Google Scholar 

  31. Haywood AF, Merner ND, Hodgkinson KA, Houston J, Syrris P, Booth V et al. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada. Eur Heart J 2013; 34: 1002–1011.

    Article  CAS  Google Scholar 

  32. Sun J, Lin X . Beta-arrestin 2 is required for lysophosphatidic acid-induced NF-kappaB activation. Proc Natl Acad Sci USA 2008; 105: 17085–17090.

    Article  CAS  Google Scholar 

  33. Blonska M, Shambharkar PB, Kobayashi M, Zhang D, Sakurai H, Su B et al. TAK1 is recruited to the tumor necrosis factor-alpha (TNF-alpha) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-kappaB activation. J Biol Chem 2005; 280: 43056–43063.

    Article  CAS  Google Scholar 

  34. Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF . An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg 2000; 92: 326–333.

    Article  CAS  Google Scholar 

  35. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65: 3307–3318.

    Article  CAS  Google Scholar 

  36. Li B, Dewey CN . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinf 2011; 12: 323.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partially supported by grants from the National Natural Science Foundation of China (81570211), Cancer Prevention Research Institute of Texas (RP120316) and National Institutes of Health (R01 AI116722) to X Lin.

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Correspondence to C Jiang or X Lin.

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Jiang, C., Zhu, Y., Zhou, Z. et al. TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression. Oncogene 36, 2813–2823 (2017). https://doi.org/10.1038/onc.2016.430

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