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Prepublished online as a Blood First Edition Paper on June 5, 2003; DOI 10.1182/blood-2002-12-3805. This Article Full Text (PDF) All Versions of this Article: 2002-12-3805v1 102/6/2122    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Feng, S. Articles by Kroll, M. H Search for Related Content PubMed PubMed Citation Articles by Feng, S. Articles by Kroll, M. H Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted December 17, 2002 Accepted May 20, 2003 Filamin A binding to the cytoplasmic tail of glycoprotein Ib regulates von Willebrand factor-induced platelet activation Shuju Feng, Julio C Resendiz, Xin Lu, and Michael H Kroll* Department of Thrombosis Research, VA Medical Center, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Biomedical Engineering, Rice University, Houston, TX, USA Wihuri Research Institute, Helsinki, Finland * Corresponding author; email: mkroll{at}bcm.tmc.edu. We examined the hypothesis that filamin A binding to the cytoplasmic tail of platelet glycoprotein (Gp) Ib is regulated by pathological shear stress and modulates von Willebrand factor (VWF)-induced platelet activation. To begin, we examined filamin binding to GpIb in Chinese hamster ovary cells co-expressing mutant human GpIb-IX and wild-type human filamin A. We observe that many different deletions and truncations N-terminal to GpIb's cytoplasmic domain residue 594 disrupt filamin A binding, but that binding is unaffected by 14 different point mutations in hydrophilic residues between amino acids 557 and 593. To try to narrow GpIb's filamin A binding domain, we next measured the effect of several cytoplasmic domain peptides on human filamin A binding to a GST-GpIb cytoplasmic domain fusion protein. One peptide (residues 557-575; designated "A4 peptide") inhibits filamin A binding to the GST-GpIb cytoplasmic domain fusion protein and competes with GpIb for binding to filamin A. When the A4 peptide is delivered to intact human platelets using a carrier peptide, we observe the dose-dependent inhibition of VWF-induced platelet aggregation in response to both ristocetin and shear stress. The effect of the A4 peptide on shear-induced platelet aggregation is accompanied by the attenuation of shear-induced filamin A binding to GpIb and diminished shear-dependent protein tyrosine phosphorylation. These results suggest that shear-dependent VWF-induced platelet activation affects filamin A binding to GpIb-IX-V, and that filamin A binding to the cytoplasmic tail of GpIb regulates proaggregatory tyrosine kinase signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: GPIb, filamin, and platelet activation: a view from within Susan L. Cranmer and Shaun P. Jackson Blood 2003 102: 1937. [Full Text] [PDF] This article has been cited by other articles: L.-J. Armstrong, V. L. Heath, S. Sanderson, S. Kaur, J. F.J. Beesley, J. M.J. Herbert, J. A. Legg, R. Poulsom, and R. 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