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• W2034995931 abstract "To understand the role of thrombin in inflammation, we tested its effects on migration of THP-1 cells, a human monocytic cell line. Thrombin induced THP-1 cell migration in a dose-dependent manner. Thrombin induced tyrosine phosphorylation of Pyk2, Gab1, and p115 RhoGEF, leading to Rac1- and RhoA-dependent Pak2 activation. Downstream to Pyk2, Gab1 formed a complex with p115 RhoGEF involving their pleckstrin homology domains. Furthermore, inhibition or depletion of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, or Pak2 levels substantially attenuated thrombin-induced THP-1 cell F-actin cytoskeletal remodeling and migration. Inhibition or depletion of PAR1 also blocked thrombin-induced activation of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, and Pak2, resulting in diminished THP-1 cell F-actin cytoskeletal remodeling and migration. Similarly, depletion of Gα12 negated thrombin-induced Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, and Pak2 activation, leading to attenuation of THP-1 cell F-actin cytoskeletal remodeling and migration. These novel observations reveal that thrombin induces monocyte/macrophage migration via PAR1-Gα12-dependent Pyk2-mediated Gab1 and p115 RhoGEF interactions, leading to Rac1- and RhoA-targeted Pak2 activation. Thus, these findings provide mechanistic evidence for the role of thrombin and its receptor PAR1 in inflammation.Background: The major goal of this study is to test the hypothesis that thrombin plays a role in inflammation.Results: Thrombin stimulates monocyte F-actin cytoskeletal remodeling and migration by PAR1, Gα12, Pyk2, Gab1, Rac1, and RhoA-dependent Pak2 activation.Conclusion: Pak2 mediates thrombin-PAR1-induced monocyte/macrophage migration.Significance: PAR1 could be a potential target for the development of anti-inflammatory drugs. To understand the role of thrombin in inflammation, we tested its effects on migration of THP-1 cells, a human monocytic cell line. Thrombin induced THP-1 cell migration in a dose-dependent manner. Thrombin induced tyrosine phosphorylation of Pyk2, Gab1, and p115 RhoGEF, leading to Rac1- and RhoA-dependent Pak2 activation. Downstream to Pyk2, Gab1 formed a complex with p115 RhoGEF involving their pleckstrin homology domains. Furthermore, inhibition or depletion of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, or Pak2 levels substantially attenuated thrombin-induced THP-1 cell F-actin cytoskeletal remodeling and migration. Inhibition or depletion of PAR1 also blocked thrombin-induced activation of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, and Pak2, resulting in diminished THP-1 cell F-actin cytoskeletal remodeling and migration. Similarly, depletion of Gα12 negated thrombin-induced Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, and Pak2 activation, leading to attenuation of THP-1 cell F-actin cytoskeletal remodeling and migration. These novel observations reveal that thrombin induces monocyte/macrophage migration via PAR1-Gα12-dependent Pyk2-mediated Gab1 and p115 RhoGEF interactions, leading to Rac1- and RhoA-targeted Pak2 activation. Thus, these findings provide mechanistic evidence for the role of thrombin and its receptor PAR1 in inflammation. Background: The major goal of this study is to test the hypothesis that thrombin plays a role in inflammation. Results: Thrombin stimulates monocyte F-actin cytoskeletal remodeling and migration by PAR1, Gα12, Pyk2, Gab1, Rac1, and RhoA-dependent Pak2 activation. Conclusion: Pak2 mediates thrombin-PAR1-induced monocyte/macrophage migration. Significance: PAR1 could be a potential target for the development of anti-inflammatory drugs. Withdrawal: Novel role for p21-activated kinase 2 in thrombin-induced monocyte migrationJournal of Biological ChemistryVol. 298Issue 5PreviewThis article has been withdrawn by the authors. The Journal states that the immunoblots corresponding to ‘Rac1’ in figure 4B and 4H were duplicated. The immunoblots corresponding to ‘beta-Tubulin’ in figure 4B and ‘Pak2’ in figure 5E were duplicated. Possible micrograph reuse for ‘RhoA ASO3 + Thrombin’ panel in figure 4C and ‘Control ASO’ panel in figure 10D. Additional potential reuse in ‘Pak2 ASO2 + Thrombin’ panel in figure 5C and ‘G-alpha-qASO2’ panel in figure 10D. Possible reuse in immunoblot panels for ‘GTP-RhoA’ in figure 4E and ‘GTP-Rac1’ in figure 10J. Full-Text PDF Open Access" @default.
• W2034995931 created "2016-06-24" @default.
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• W2034995931 date "2013-10-01" @default.
• W2034995931 modified "2023-09-27" @default.
• W2034995931 title "Novel Role for p21-activated Kinase 2 in Thrombin-induced Monocyte Migration" @default.
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• W2034995931 doi "https://doi.org/10.1074/jbc.m113.463414" @default.
• W2034995931 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3829397" @default.
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• W2034995931 hasPublicationYear "2013" @default.
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