Protein phosphatase type 2A, PP2A, is involved in degradation of gp130.

Abstract

The interleukin-6 (IL-6) stimulates growth in cells such as multiple myeloma and B-cell plasmacytomas/hybridomas, while it inhibits growth in several myeloid leukemia cells. The IL-6 receptor has subunit called gp130. It was reported that Ser-782 of gp130 is phosphorylated by unidentified kinase(s) in cell extracts, and level of gp130 (S782A) transiently expressed on the cell surface of COS-7 is 6-times higher than that of the wild type. These results motivated us to analyze whether the phosphorylation of gp130 at Ser-782 is involved in its degradation or not. In this study, we demonstrated here that treatment of HepG2 cells with okadaic acid (OA), a potent inhibitor for PP2A, promotes phosphorylation of gp 130 at Ser-782 and degradation of gp 130. MG115, a proteasome inhibitor, suppressed this degradation. These effects of OA could not be replaced with tautomycetin (TC), an inhibitor for PP1. Purified PP2A dephosphorylated phospho-Ser-782 of gp130 in vitro. IL-6-induced activation of Stat3 was suppressed by preincubation of the cells with OA, suggesting that the IL-6 signaling pathway was blocked by OA through degradation of gp 130. Taken together, present results strongly suggest that degradation of gp 130 is regulated through a phosphorylation-dephosphorylation mechanism in which PP2A is crucially involved and that gp 130 is a potential therapeutic target in cancers.

• Authors: Shinya Mitsuhashi, Hiroshi Shima, Nobuhiro Tanuma, Sumie Sasa, Kazunori Onoe, Makoto Ubukata, Kunimi Kikuchi
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 269 Issue 1-2 Pg. 183-7 (Jan 2005) ISSN: 0300-8177 [Print] Netherlands
• PMID: 15786731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• IL6ST protein, human
• Interleukin-6
• Leupeptins
• Membrane Glycoproteins
• Protease Inhibitors
• Proteasome Inhibitors
• RNA, Messenger
• carbobenzoxy-leucyl-leucyl-norvalinal
• Cytokine Receptor gp130
• Okadaic Acid
• Serine
• Phosphoprotein Phosphatases

Topics

• Antigens, CD (genetics, metabolism)
• Cytokine Receptor gp130
• Gene Expression
• Humans
• Interleukin-6 (metabolism, pharmacology)
• Leupeptins (pharmacology)
• Membrane Glycoproteins (genetics, metabolism)
• Okadaic Acid (pharmacology)
• Phosphoprotein Phosphatases (antagonists & inhibitors, genetics, physiology)
• Phosphorylation
• Protease Inhibitors (pharmacology)
• Proteasome Inhibitors
• RNA, Messenger (metabolism)
• Serine (metabolism)
• Tumor Cells, Cultured