Annexin A6 is a scaffold for PKCa to promote EGFR inactivation
| Autor: | Katia Monastyrskaya, Rose Cairns, Meritxell Reverter, Carlos Enrich, Anna Alvarez-Guaita, Monira Hoque, William E. Hughes, Francesc Tebar, Peta Wood, Thomas Grewal, Alexander Swarbrick, Carles Rentero, S Vilá de Muga, Roger J. Daly, B P Kota, Meryem Koese |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Protein Kinase C-alpha 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Annexin Cell Line Tumor Genetics Humans Epidermal growth factor receptor Annexin A6 Phosphorylation Protein kinase A Molecular Biology 030304 developmental biology Cell Proliferation 0303 health sciences biology Cell growth Cell Membrane Tyrosine phosphorylation ErbB Receptors Protein Transport chemistry 030220 oncology & carcinogenesis Gene Knockdown Techniques Proteolysis Cancer research biology.protein Tyrosine RNA Interference Signal transduction A431 cells Protein Processing Post-Translational Protein Binding Signal Transduction |
| Zdroj: | Oncogene |
| DOI: | 10.1038/onc.2012.303 |
| Popis: | Protein kinase Ca (PKCa) 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 PKCa in a large variety of cancers is not associated with EGFR inactivation and factors determining the potential of PKCa to downregulate EGFR are yet unknown. Here we show that ectopic expression of annexin A6 (AnxA6) a member of the Ca(2+) 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 PKCa 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 PKCa membrane association and interaction with EGFR. Stable expression of the cytosolic N terminal mutant AnxA6(1 175) which cannot promote PKCa membrane recruitment does not increase T654 EGFR phosphorylation or the association of PKCa with EGFR. AnxA6 overexpression does not inhibit tyrosine phosphorylation of the T654A EGFR mutant which cannot be phosphorylated by PKCa. Most strikingly stable plasma membrane anchoring of AnxA6 is sufficient to recruit PKCa even in the absence of EGF or Ca(2+). In summary AnxA6 is a new PKCa scaffold to promote PKCa mediated EGFR inactivation through increased membrane targeting of PKCa and EGFR/PKCa complex formation.Oncogene advance online publication 16 July 2012; doi:10.1038/onc.2012.303. |
| Databáze: | OpenAIRE |
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