Role of Cholesterol in Formation and Function of a Signaling Complex Involving vß3, Integrin-associated Protein (CD47), and Heterotrimeric G Proteins

Correspondence to: Eric J. Brown, Center for Host/Pathogen Interactions, University of California, San Francisco, HSE 201, Campus Box 0513, 513 Parnassus Avenue, San Francisco, CA 94143-0513. Tel:(415) 514-0167 Fax:(415) 514-0169 E-mail:ebrown{at}medicine.ucsf.edu.

Integrin-associated protein (CD47) is a multiply membrane spanning member of the immunoglobulin superfamily that regulates some adhesion-dependent cell functions through formation of a complex with vß3 integrin and trimeric G proteins. Cholesterol is critical for the association of the three protein components of the supramolecular complex and for its signaling. The multiply membrane spanning domain of IAP is required for complex formation because it binds cholesterol. The supramolecular complex forms preferentially in glycosphingolipid-enriched membrane domains. Binding of mAb 10G2 to the IAP Ig domain, previously shown to be required for association with vß3, is affected by both the multiply membrane spanning domain and cholesterol. These data demonstrate that cholesterol is an essential component of the vß3/IAP/G protein signaling complex, presumably acting through an effect on IAP conformation.

Key Words: cholesterol, integrin, cell adhesion, plasma membrane, vitronectin

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