A protein tyrosine phosphatase inhibitor, pervanadate, inhibits angiotensin II-Induced beta-arrestin cleavage
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Published on: June 27, 2015
Sei-Heon Jang1, Si Ae Hwang, Mijin Kim
1Department of Molecular Biology, Daegu University, Gyeongsan 712-714, Korea.
Abstract:
Beta-arrestins turn off G protein-mediated signals and initiate distinct G protein-independent signaling pathways. We previously demonstrated that angiotensin AT(1) receptor-bound beta-arrestin 1 is cleaved after Phe(388) upon angiotensin II stimulation. The mechanism and signaling pathway of angiotensin II-induced beta-arrestin cleavage remain largely unknown. Here, we show that protein Tyr phosphatase activity is involved in the regulation of beta-arrestin 1 cleavage. Tagging of green fluorescent protein (GFP) either to the N-terminus or C-terminus of beta-arrestin 1 induced conformational changes and the cleavage of beta-arrestin 1 without angiotensin AT(1) receptor activation. Orthovanadate and molybdate, inhibitors of protein Tyr phosphatase, attenuated the cleavage of C-terminal GFP-tagged beta-arrestin 1 in vitro. The inhibitory effects of okadaic acid and pyrophosphate, which are inhibitors of protein Ser/Thr phosphatase, were less than those of protein Tyr phosphatase inhibitors. Cell-permeable pervanadate inhibited angiotensin II-induced cleavage of beta-arrestin 1 in COS-1 cells. Our findings suggest that Tyr phosphorylation signaling is involved in the regulation of angiotensin II-induced beta-arrestin cleavage.
Insights
Beta-arrestin 1 cleavage, crucial for turning off signals, is regulated by protein tyrosine phosphatase activity. This finding reveals a new mechanism in angiotensin signaling pathways.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- Beta-arrestins are key regulators of G protein-coupled receptor signaling, mediating signal termination and initiating distinct pathways.
- Angiotensin II stimulation leads to the cleavage of beta-arrestin 1, but the underlying mechanism remains unclear.
Purpose of the Study:
- To investigate the signaling pathways involved in angiotensin II-induced beta-arrestin 1 cleavage.
- To determine the role of protein phosphatases in regulating beta-arrestin 1 cleavage.
Main Methods:
- Investigated beta-arrestin 1 cleavage using green fluorescent protein (GFP) tagging.
- Utilized protein tyrosine phosphatase inhibitors (orthovanadate, molybdate, pervanadate) and protein serine/threonine phosphatase inhibitors (okadaic acid, pyrophosphate).
- Assessed cleavage in vitro and in COS-1 cells stimulated with angiotensin II.
Main Results:
- GFP tagging of beta-arrestin 1 induced cleavage independently of angiotensin AT(1) receptor activation.
- Protein tyrosine phosphatase inhibitors significantly attenuated beta-arrestin 1 cleavage.
- Protein serine/threonine phosphatase inhibitors showed less effect on beta-arrestin 1 cleavage.
Conclusions:
- Protein tyrosine phosphatase activity plays a regulatory role in angiotensin II-induced beta-arrestin 1 cleavage.
- Tyr phosphorylation signaling is implicated in the mechanism of beta-arrestin 1 cleavage.
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