Journal
BLOOD CELLS MOLECULES AND DISEASES
Volume 38, Issue 3, Pages 269-279Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bcmd.2007.01.002
Keywords
platelet; lysophosphatidic; shape change; secretion; actin; rho-kinase; PAK; LIM-kinase; cofilin; phosphatase
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Cofilin is an actin dynamizing protein and inactivated after Ser3 phosphorylation by LIM-kinases (LIMKs). We studied whether in platelets stimulated by lysophosphatidic acid (LPA), Rho-kinase or p21-activated kinase (PAK) mediates LIMK-l activation leading to subsequent phosphorylation and inactivation of cofilin and the increase of F-actin. During LPA (0.1 mu M)-induced shape change, a rapid Rho-kinase activation and a slower activation of PAK were observed. Rho-kinase activation led to rapid LIMK-I (Thr508) phosphorylation. Despite of LIMK-I activation, cofilin net phosphorylation was not increased. Cofilin rapidly associated with F-actin and preceded the F-actin increase. Pretreatment with the Rhokinase inhibitor Y-27632 inhibited LIMK-1 phosphorylation, unmasked cofilin dephosphorylation and inhibited the reversible F-actin increase during shape change. In the presence of fibrinogen, LPA (10 mu M) induced ATP-secretion from dense granules and aggregation, and cofilin was rapidly dephosphorylated and then rephosphorylated in a Rho-kinase/LIMK-1-dependent manner. In the absence of fibrinogen, cofilin de- and rephosphorylation after LPA (10 mu M) was unchanged, but secretion and aggregation were absent. Cofilin dephosphorylation was completely blocked by BAPTA-AM indicating that it was mediated by an increase of cytosolic Ca2+. We conclude that in LPA-stimulated platelets, Rho-kinase dependent LIMK-1 activation mediates the F-actin increase during shape change without enhancing cofilin net phosphorylation. However, a rapid dephosphorylation of cofilin occurs during secretion and aggregation, which is Ca2+ dependent, upstream of secretion and aggregation and might regulate these platelet responses. (c) 2007 Elsevier Inc. All rights reserved.
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