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Unraveling a novel Rac1-mediated signaling pathway that regulates cofilin dephosphorylation and secretion in thrombin-stimulated platelets
| Content Provider | Scilit |
|---|---|
| Author | Pandey, Dharmendra Goyal, Pankaj Dwivedi, Suman Siess, Wolfgang |
| Copyright Year | 2009 |
| Description | In platelets stimulated by thrombin to secrete and aggregate, cofilin is rapidly dephosphorylated leading to its activation. Cofilin by severing existing actin filaments and stimulating F-actin polymerization on newly created barbed ends dynamizes the actin cytoskeleton. We previously found that cofilin dephosphorylation is Ca2+-dependent and occurs upstream of degranulation in stimulated platelets. We report now in thrombin-stimulated platelets that Rac1 and class II PAKs (PAK4/5/6) were rapidly (within 5 seconds) activated, whereas PAK1/2 (class I PAKs) phosphorylation was slower. The Rac1-specific inhibitor NSC23766 blocked phosphorylation of class II PAKs, but not PAK1/2. Moreover, inhibition of the Ca2+/calmodulin-dependent phosphatase calcineurin inhibited Rac1 activation and class II PAKs phosphorylation. Prevention of Rac1 activation by calcineurin inhibition or NSC23766 also blocked cofilin dephosphorylation and platelet granule secretion indicating that a calcineurin/Rac1/class II PAKs pathway regulates cofilin dephosphorylation leading to secretion. We further found that PI3-kinases were activated downstream of Rac1, but were not involved in regulating cofilin dephosphorylation and secretion in thrombin-stimulated platelets. Our study unravels a Ca2+-dependent pathway of secretion in stimulated platelets as a signaling pathway linking Rac1 activation to actin dynamics: calcineurin→Rac1→class II PAKs→cofilin activation. We further demonstrate that this pathway is separate and independent of the protein kinase C (PKC) pathway mediating secretion. |
| Related Links | http://www.bloodjournal.org/content/bloodjournal/114/2/415.full.pdf |
| Ending Page | 424 |
| Page Count | 10 |
| Starting Page | 415 |
| DOI | 10.1182/blood-2008-10-183582 |
| Journal | Blood |
| Issue Number | 2 |
| Volume Number | 114 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2009-07-09 |
| Access Restriction | Open |
| Subject Keyword | Biochemistry and Molecular Biology Research and Experimental Medicine Signaling Pathway Journal: Blood (Vol- 60, Issue- 2) |
| Content Type | Text |
| Resource Type | Article |
