Regulation of apoptosis by Bat3-enhanced YWK-II/APLP2 protein stability

J Cell Sci. 2012 Sep 15;125(Pt 18):4219-29. doi: 10.1242/jcs.086553. Epub 2012 May 28.


YWK-II protein/APLP2 is a member of an evolutionarily conserved protein family that includes amyloid precursor protein (APP) and amyloid precursor-like protein-1 (APLP1). We have previously demonstrated that YWK-II/APLP2 functions as a novel G(0)-protein-coupled receptor for Müllerian inhibiting substance (MIS) in cell survival. However, factors regulating the stability and turnover of YWK-II/APLP2 have not been identified. Here we present evidence that human leukocyte antigen-B-associated transcript 3 (Bat3), an important regulator involved in apoptosis, can interact with YWK-II/APLP2 and enhance its stability by reducing its ubiquitylation and degradation by the ubiquitin-proteasome system. Coexpression of different Bat3 domain deletion constructs with YWK-II/APLP2 reveals that the proline-rich domain of Bat3 is required for its binding to YWK-II/APLP2. In addition, we find that the protein levels of YWK-II/APLP2 could be enhanced by nuclear export of Bat3 under apoptotic stimulation. We also find elevated levels of Bat3 and YWK-II/APLP2 in human colorectal cancer with a positive correlation between the two. Taken together, these results have revealed a previously undefined mechanism regulating cell apoptosis and suggest that aberrant enhancement of YWK-II/APLP2 by nuclear export of Bat3 may play a role in cancer development by inhibiting cell apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Apoptosis*
  • CHO Cells
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Cricetinae
  • Cricetulus
  • Female
  • Gene Knockdown Techniques
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Molecular Chaperones / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Protein Stability
  • Ubiquitination
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • APLP2 protein, human
  • Amyloid beta-Protein Precursor
  • BAG6 protein, human
  • Molecular Chaperones
  • Nerve Tissue Proteins