Regulation of apoptosis by Bat3-enhanced YWK-II/APLP2 protein stability.
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.
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University 5 Dong Dan San Tiao, Beijing 100005, China.
Wei
W
Wu
Wei
W
Song
Shuchun
S
Li
Songying
S
Ouyang
Kin Lam
KL
Fok
Ruiying
R
Diao
Shiying
S
Miao
Hsiao Chang
HC
Chan
Linfang
L
Wang
D021581:Active Transport, Cell Nucleus; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D054875:Ubiquitination; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; C092009:BAG6 protein, human; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins