Protein phosphatase type 2A, PP2A, is involved in degradation of gp130.
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.
Mitsuhashi
Shinya
S
Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, Japan.
Shima
Hiroshi
H
Tanuma
Nobuhiro
N
Sasa
Sumie
S
Onoe
Kazunori
K
Ubukata
Makoto
M
Kikuchi
Kunimi
K
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D050822:Cytokine Receptor gp130; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C494199:IL6ST protein, human; D015850:Interleukin-6; D007976:Leupeptins; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D050822:Cytokine Receptor gp130; D019319:Okadaic Acid; D012694:Serine; D010749:Phosphoprotein Phosphatases