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J. Biol. Chem., Vol. 279, Issue 26, 27286-27293, June 25, 2004

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ICln, a Novel Integrin _IIb3-Associated Protein, Functionally Regulates Platelet Activation^*

Deirdre Larkin, Derek Murphy, Dermot F. Reilly, Martha Cahill, Ellen Sattler, Pat Harriott¶, Dolores J. Cahill, and Niamh Moran||

From the Department of Clinical Pharmacology and the Centre for Human Proteomics, Royal College of Surgeons in Ireland, Dublin 2 and the ^¶Medical Biology Centre, Queens University Belfast, Belfast BT9 7BL, Ireland

A critical role for the conserved -integrin cytoplasmic motif, KVGFFKR, is recognized in the regulation of activation of the platelet integrin _IIb3. To understand the molecular mechanisms of this regulation, we sought to determine the nature of the protein interactions with this cytoplasmic motif. We used a tagged synthetic peptide, biotin-KVGFFKR, to probe a high density protein expression array (37,200 recombinant human proteins) for high affinity interactions. A number of potential integrin-binding proteins were identified. One such protein, a chloride channel regulatory protein, ICln, was characterized further because its affinity for the integrin peptide was highest as was its expression in platelets. We verified the presence of ICln in human platelets by PCR, Western blots, immunohistochemistry, and its co-association with _IIb3 by surface plasmon resonance. The affinity of this interaction was 82.2 ± 24.4 nM in a cell free assay. ICln co-immunoprecipitates with _IIb3 in platelet lysates demonstrating that this interaction is physiologically relevant. Furthermore, immobilized KVGFFKR peptides, but not control KAAAAAR peptides, specifically extract ICln from platelet lysates. Acyclovir (100 µM to 5 mM), a pharmacological inhibitor of the ICln chloride channel, specifically inhibits integrin activation (PAC-1 expression) and platelet aggregation without affecting CD62 P expression confirming a specific role for ICln in integrin activation. In parallel, a cell-permeable peptide corresponding to the potential integrin-recognition domain on ICln (AKFEEE, 10–100 µM) also inhibits platelet function. Thus, we have identified, verified, and characterized a novel functional interaction between the platelet integrin and ICln, in the platelet membrane.

Received for publication, February 26, 2004 , and in revised form, April 8, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 353-1-402-2153; Fax: 353-1-402-2453; E-mail: nmoran{at}rcsi.ie.

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