Annexin A6 is a scaffold for PKC? to promote EGFR inactivation.
Protein kinase C? (PKC?) 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 PKC? in a large variety of cancers is not associated with EGFR inactivation, and factors determining the potential of PKC? 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, breast cancer and head and neck cancer cell lines. Conversely, AnxA6 knockdown increases EGFR tyrosine phosphorylation, while T654-EGFR phosphorylation is reduced. AnxA6 overexpression does not inhibit tyrosine phosphorylation of the T654A EGFR mutant, which cannot be phosphorylated by PKC?. RNAi-mediated PKC? knockdown restores EGFR tyrosine phosphorylation and clonogenic growth in AnxA6 expressing A431 cells. These findings correlate with AnxA6 interacting with EGFR, and elevated AnxA6 levels promoting PKC? membrane association and interaction with EGFR. Most strikingly, stable plasma membrane anchoring of AnxA6 is sufficient to recruit PKC? even in the absence of EGF or Ca2+. In summary, AnxA6 is a new PKC? scaffold to promote PKC?-mediated EGFR inactivation through increased membrane targeting of PKC? and EGFR/PKC? complex formation.
|Authors||Koese, M.; Rentero, C.; Vila de Muga, S.; Kota, B.P.; Wood, P.; Cains, R.; Reverter, M.; Alvarez-Guaita, A.; Monastyrskaya, K.; Hughes, W.E.; Tebar, F.; Daly, R.J.; Enrich, C.; Grewal, T.|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22797061|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11144|