Epidermal Growth Factor Receptor activation promotes ADA3 acetylation through the AKT-p300 pathway

Shashank Srivastava, Shakur Mohibi, Sameer Mirza, Hamid Band, Vimla Band

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The ADA3 (Alteration/Deficiency in Activation 3) protein is an essential adaptor component of several Lysine Acetyltransferase (KAT) complexes involved in chromatin modifications. Previously, we and others have demonstrated a crucial role of ADA3 in cell cycle progression and in maintenance of genomic stability. Recently, we have shown that acetylation of ADA3 is key to its role in cell cycle progression. Here, we demonstrate that AKT activation downstream of Epidermal Growth Factor Receptor (EGFR) family proteins stimulation leads to phosphorylation of p300, which in turn promotes the acetylation of ADA3. Inhibition of upstream receptor tyrosine kinases (RTKs), HER1 (EGFR)/HER2 by lapatinib and the accompanying reduction of phospho-AKT levels led to a decrease in p300 phosphorylation and ADA3 protein levels. The p300/PCAF inhibitor garcinol also destabilized the ADA3 protein in a proteasome-dependent manner and an ADA3 mutant with K→R mutations exhibited a marked increase in half-life, consistent with opposite role of acetylation and ubiquitination of ADA3 on shared lysine residues. ADA3 knockdown led to cell cycle inhibitory effects, as well as apoptosis similar to those induced by lapatinib treatment of HER2+ breast cancer cells, as seen by accumulation of CDK inhibitor p27, reduction in mitotic marker pH3(S10), and a decrease in the S-phase marker PCNA, as well as the appearance of cleaved PARP. Taken together our results reveal a novel RTK-AKT-p300-ADA3 signaling pathway involved in growth factor-induced cell cycle progression.

Original languageEnglish (US)
Pages (from-to)1515-1525
Number of pages11
JournalCell Cycle
Volume16
Issue number16
DOIs
StatePublished - Aug 18 2017

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Keywords

  • ADA3
  • AKT
  • HAT complex
  • HER2
  • SAGA complex
  • acetylation
  • lapatinib
  • p300
  • phosphorylation
  • ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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