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 Prepublished online as a Blood First Edition Paper on April 3, 2003; DOI 10.1182/blood-2002-09-2897.

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Submitted September 24, 2002
Accepted March 27, 2003

SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V. Localization of SHIP-2 to the activated platelet actin cytoskeleton.

Jennifer M Dyson, Adam D Munday, Anne M Kong, Richard D Huysmans, Maria Matzaris, Meredith J Layton, Harshal H Nandurkar, Michael C Berndt, and Christina A Mitchell*

Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research, Melbourne, VIC, Australia
Joint Protein Structure Laboratory, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

* Corresponding author; email: christina.mitchell{at}med.monash.edu.au.

The platelet receptor for von Willebrand factor (vWF) glycoprotein (GP)Ib-IX-V complex mediates platelet adhesion at sites of vascular injury. The cytoplasmic tail of the GPIba subunit interacts with the actin-binding protein, filamin, anchoring the receptor in the cytoskeleton. In motile cells, the second messenger PtdIns(3,4,5)P3 induces submembraneous actin remodelling. The inositol polyphosphate 5-phosphatase, SHIP-2, hydrolyzes phosphoinositide 3,4,5 trisphosphate (PtdIns(3,4,5)P3) forming PtdIns(3,4)P2, and regulates membrane ruffling via complex formation with filamin (Dyson et al., J. Cell. Biol 2001 155(6) 1065-1079). In this study we investigate the intracellular location and association of SHIP-2 with filamin, actin, and the GPIb-IX-V complex in platelets. Immunoprecipitation of SHIP-2 from the Triton-soluble fraction of unstimulated platelets demonstrated association between SHIP-2, filamin, actin and GPIb-IX-V. SHIP-2 associated with filamin or GPIb-IX-V, was active, and demonstrated PtdIns(3,4,5)P3 5-phosphatase activity. Following thrombin or vWF-induced platelet activation, detection of the SHIP-2, filamin and receptor complex decreased in the Triton-soluble fraction, although in control studies the level of SHIP-2, filamin, or GP1b-IX-V immunopreciptated by their respective antibodies did not change following platelet activation. In activated platelets spreading on a vWF matrix, SHIP-2 localized intensely with actin at the central actin ring and co-localized with actin and filamin at filopodia and lamellipodia. In spread platelets, GPIb-IX-V localized to the centre of the platelet and showed little co-localization with filamin at the plasma membrane. These studies demonstrate a functionally active complex between SHIP-2, filamin, actin and GPIb-IX-V which may orchestrate the localized hydrolysis of PtdIns(3,4,5)P3 and thereby regulate cortical and submembraneous actin.


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