Regulation of acidification and apoptosis by SHP-1 and Bcl-2

被引:95
作者
Thangaraju, M
Sharma, K
Leber, B
Andrews, DW
Shen, SH
Srikant, CB
机构
[1] Royal Victoria Hosp, Montreal, PQ H3A 1A1, Canada
[2] McGill Univ, Dept Med, Fraser Labs, Montreal, PQ H3A 1A1, Canada
[3] McMaster Univ, Hlth Sci Ctr, Dept Biochem, Hamilton, ON L8N 325, Canada
[4] McMaster Univ, Hlth Sci Ctr, Dept Med, Hamilton, ON L8N 325, Canada
[5] Natl Res Council Canada, Biotechnol Res Inst, Pharmacol Sector, Montreal, PQ H4P 2R2, Canada
关键词
D O I
10.1074/jbc.274.41.29549
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recruitment of the SH2 domain containing cytoplasmic protein-tyrosine phosphatase SHP-1 to the membrane by somatostatin (SST) is an early event in its antiproliferative signaling that induces intracellular acidification-dependent apoptosis in breast cancer cells. Fas ligation also induces acidification-dependent apoptosis in a manner requiring the presence of SHP-1 at the membrane. Moreover, we have recently reported that SRP-I is required not only for acidification, but also for apoptotic events that follow acidification (Thangaraju, M., Sharma, K., Liu, D., Shen, S. H., and Srikant, C. B. (1999) Cancer Res. 59, 1649-1654). Here we show that ectopically expressed SHP-1 was predominantly membrane-associated and amplified the cytotoxic signaling initiated upon SST receptor activation and Fas ligation. The catalytically inactive mutant of SHP-1 (SHP-1C455S) abolished the ability of the SST agonists to signal apoptosis by preventing the recruitment of wild type SHP-1 to the membrane. Overexpression of the anti-apoptotic protein Bcl-2 in MCF-7 cells inhibited SST-induced apoptosis upstream of acidification by inhibiting p53-dependent induction of Bax as well as by raising the resting pH(i) and attenuating SST-induced decrease in pH. By contrast, Bcl-2 failed to prevent apoptosis triggered by direct acidification. These data demonstrate that (i) membrane-associated SHP-1 is required for receptor-mediated cytotoxic signaling that causes intracellular acidification and apo ptosis, and (ii) Bcl-2 acts distal to SHP-1 and p53 to prevent SST-induced acidification but cannot inhibit the apoptotic events that ensue intracellular acidification.
引用
收藏
页码:29549 / 29557
页数:9
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