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Annexin A6 is a scaffold for PKCα to promote EGFR inactivation

Oncogene volume 32, pages 2858–2872 (2013)Cite this article

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Abstract

Protein kinase Cα (PKCα) can phosphorylate the epidermal growth factor receptor (EGFR) at threonine 654 (T654) to inhibit EGFR tyrosine phosphorylation (pY-EGFR) and the associated activation of downstream effectors. However, upregulation of PKCα in a large variety of cancers is not associated with EGFR inactivation, and factors determining the potential of PKCα to downregulate EGFR are yet unknown. Here, we show that ectopic expression of annexin A6 (AnxA6), a member of the Ca2+ and phospholipid-binding annexins, strongly reduces pY-EGFR levels while augmenting EGFR T654 phosphorylation in EGFR overexpressing A431, head and neck and breast cancer cell lines. Reduced EGFR activation in AnxA6 expressing A431 cells is associated with reduced EGFR internalization and degradation. RNA interference (RNAi)-mediated PKCα knockdown in AnxA6 expressing A431 cells reduces T654-EGFR phosphorylation, but restores EGFR tyrosine phosphorylation, clonogenic growth and EGFR degradation. These findings correlate with AnxA6 interacting with EGFR, and elevated AnxA6 levels promoting PKCα membrane association and interaction with EGFR. Stable expression of the cytosolic N-terminal mutant AnxA61–175, which cannot promote PKCα membrane recruitment, does not increase T654-EGFR phosphorylation or the association of PKCα with EGFR. AnxA6 overexpression does not inhibit tyrosine phosphorylation of the T654A EGFR mutant, which cannot be phosphorylated by PKCα. Most strikingly, stable plasma membrane anchoring of AnxA6 is sufficient to recruit PKCα even in the absence of EGF or Ca2+. In summary, AnxA6 is a new PKCα scaffold to promote PKCα-mediated EGFR inactivation through increased membrane targeting of PKCα and EGFR/PKCα complex formation.

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Acknowledgements

This study was supported by grants to TG from the National Health and Medical Research Council of Australia (NHMRC; 510293, 510294) and the University of Sydney (2010-02681). CE is supported by BFU2009-10335, Consolider-Ingenio CSD2009-00016 from Ministerio de Innovación, Ciencia y Tecnología and PI040236 from Fundació Marató TV3 (Barcelona, Spain). FT is supported by BFU2009-13526. RJD and AS would like to acknowledge funding from the NHMRC. PW is a recipient of a co-funded National Heart Foundation (NHF)/NHMRC postgraduate scholarship. CR is grateful to the Beatriu de Pinós fellowship (Generalitat de Catalunya). SV is thankful to Ministerio de Educación y Ciencia, Spain, (FPI mobility Program) for a short-term fellowship at the laboratory of TG (Sydney, Australia). MR and AA are supported by fellowships from Ministerio de Innovación, Ciencia y Tecnología. AS is supported by Early Career Fellowships from the Cancer Institute NSW and the National Breast Cancer Foundation.

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia

    M Koese, B P Kota, M Hoque, R Cairns, P Wood & T Grewal

  2. Departament de Biologia Cel·lular, Immunologia i Neurociències, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

    C Rentero, S Vilà de Muga, M Reverter, A Alvarez-Guaita, F Tebar & C Enrich

  3. Department of Clinical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland

    K Monastyrskaya

  4. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    W E Hughes, A Swarbrick & R J Daly

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  1. M Koese
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Koese, M., Rentero, C., Kota, B. et al. Annexin A6 is a scaffold for PKCα to promote EGFR inactivation. Oncogene 32, 2858–2872 (2013). https://doi.org/10.1038/onc.2012.303

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