Epstein-Barr virus latent membrane protein 1 mediates serine 25 phosphorylation and nuclear entry of annexin A2 via PI-PLC-PKCα/PKCβ pathway

Wei Luo, Guangrong Yan, Lili Li, Zhenlian Wang, Haidan Liu, Shanghui Zhou, Sufang Liu, Min Tang, Wei Yi, Zigang Dong, Ya Cao

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

We have previously elucidated that Epstein-Barr-virus-encoded latent membrane protein 1 (LMP1) can increase the serine phosphorylation level of annexin A2 by activating the protein kinase C (PKC) signaling pathway and that LMP1 induces the nuclear entry of annexin A2 in an energy- and temperature-dependent manner. Here, we further confirm that LMP1 increases the serine phosphorylation level of annexin A2 by activating the phosphoinositide-specific phospholipase C (PI-PLC)-PKC α/PKC β pathway, mainly through the activation of the PKCβ pathway. Additionally, active recombinant PKC α, PKC β I, and PKC β II kinases are able to phosphorylate annexin A2 in vitro. Annexin A2 in the nucleus plays an important role in DNA synthesis and cell proliferation. By site-specific substitution of glutamic acid in the place of serine 11 and 25 in the N-terminus, we show that serine 25 phosphorylation of annexin A2 was associated with the nuclear entry of annexin A2, DNA synthesis and cell proliferation, whereas serine 11 has no obvious influence. We demonstrate for the first time that the PI-PLC-PKCα/PKCβ pathway plays an important role in serine phosphorylation and in the nuclear entry of annexin A2 mediated by LMP1. In addition, we show that annexin A2 is the substrate protein of PKC α, PKC βI, and PKC bII kinases. Serine 25 phosphorylation of annexin A2 is shown to be associated with its nuclear entry, DNA synthesis, and cell proliferation.

Original languageEnglish (US)
Pages (from-to)934-946
Number of pages13
JournalMolecular Carcinogenesis
Volume47
Issue number12
DOIs
StatePublished - Dec 1 2008

Keywords

  • Annexin A2
  • Epstein-Barr virus (EBV)
  • Latent membrane protein 1 (LMP1)
  • Nasopharyngeal carcinoma (NPC)
  • Phosphoinositide-specific phospholipase C (PI-PLC)
  • Protein kinase C (PKC)

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