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

Muthusamy Thangaraju, Kamal Sharma, Brian Leber, David W. Andrews, Shi Hsiang Shen, Coimbatore B. Srikant

Research output: Contribution to journalArticle

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Abstract

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 SHP-1 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(i). 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 apoptosis, 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.

Original languageEnglish (US)
Pages (from-to)29549-29557
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number41
DOIs
StatePublished - Oct 8 1999
Externally publishedYes

Fingerprint

Acidification
Somatostatin
Apoptosis
Membranes
Ligation
SH2 Domain-Containing Protein Tyrosine Phosphatases
Somatostatin Receptors
Apoptosis Regulatory Proteins
MCF-7 Cells
Non-Receptor Type 6 Protein Tyrosine Phosphatase
Breast Neoplasms
Chemical activation
Cells
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Thangaraju, M., Sharma, K., Leber, B., Andrews, D. W., Shen, S. H., & Srikant, C. B. (1999). Regulation of acidification and apoptosis by SHP-1 and Bcl-2. Journal of Biological Chemistry, 274(41), 29549-29557. https://doi.org/10.1074/jbc.274.41.29549

Regulation of acidification and apoptosis by SHP-1 and Bcl-2. / Thangaraju, Muthusamy; Sharma, Kamal; Leber, Brian; Andrews, David W.; Shen, Shi Hsiang; Srikant, Coimbatore B.

In: Journal of Biological Chemistry, Vol. 274, No. 41, 08.10.1999, p. 29549-29557.

Research output: Contribution to journalArticle

Thangaraju, M, Sharma, K, Leber, B, Andrews, DW, Shen, SH & Srikant, CB 1999, 'Regulation of acidification and apoptosis by SHP-1 and Bcl-2', Journal of Biological Chemistry, vol. 274, no. 41, pp. 29549-29557. https://doi.org/10.1074/jbc.274.41.29549
Thangaraju, Muthusamy ; Sharma, Kamal ; Leber, Brian ; Andrews, David W. ; Shen, Shi Hsiang ; Srikant, Coimbatore B. / Regulation of acidification and apoptosis by SHP-1 and Bcl-2. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 41. pp. 29549-29557.
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