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J. Biol. Chem., Vol. 278, Issue 23, 21024-21031, June 6, 2003

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Calreticulin Is at the Surface of Circulating Neutrophils and Uses CD59 as an Adaptor Molecule^*

Ionita Ghiran  , Lloyd B. Klickstein ¶ and Anne Nicholson-Weller 

From the Divisions of Allergy-Inflammation and Infectious Disease, Beth Israel Deaconess Medical Center and the ^¶Division of Rheumatology and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Calreticulin, which has been proposed to be a C1q receptor on neutrophils, has neither a transmembrane domain nor a GPI-anchor attachment site and must utilize an adaptor molecule to attach to the plasma membrane. The expression of ecto-calreticulin on purified human neutrophils did not result from contamination by soluble or intracellular calreticulin released during cell fractionation because it was expressed on circulating neutrophils, and the expression did not increase significantly with neutrophil isolation. All neutrophils expressed calreticulin with a unimodal distribution. Treatment of neutrophils with either a cholesterol-binding agent or phosphatidylinositol-specific phospholipase C dramatically decreased ecto-calreticulin expression indicating that the adaptor molecule(s) are located in lipid rafts and have a GPI-anchor. Analysis for the co-expression of specific GPI-anchored proteins and ecto-calreticulin in cells that were deficient in specific GPI-anchored proteins, indicated that ecto-calreticulin was best associated with CD59. Calreticulin reciprocally immunoprecipited with CD59, which provided direct evidence that CD59 is an adaptor for ecto-calreticulin. Immunofluorescence and confocal microscopy demonstrated that ecto-calreticulin co-localized with a fraction of CD59 at the cell surface. Cross-linking ecto-calreticulin with antibodies induced a Ca²⁺ flux, which suggests that ecto-calreticulin is capable of signaling following ligand binding. Ecto-calreticulin has been associated with diverse cellular functions. An appreciation that the adaptors for ecto-calreticulin are GPI-anchored will provide a framework for understanding any common features underlying ecto-calreticulin ligation.

Received for publication, March 5, 2003 , and in revised form, March 19, 2003.

^* This work was funded by a Pilot/Feasibility grant (to I. G.) from the Harvard Digestive Disease Center and Grants NIH P30 DK34845 and NIH RO1 AI42987 (to A. N. W.). 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: Division of Allergy-Inflammation, Dana Bldg., Rm. 617, 330 Brookline Ave., Boston, MA 02215. E-mail: ighiran{at}bidmc.harvard.edu.

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