Specific inhibition of GPI-anchored protein function by homing and self-association of specific GPI anchors.
The functional specificity conferred by glycophosphatidylinositol (GPI) anchors on certain membrane proteins may arise from their occupancy of specific membrane microdomains. We show that membrane proteins with noninteractive external domains attached to the same carcinoembryonic antigen (CEA) GPI anchor, but not to unrelated neural cell adhesion molecule GPI anchors, colocalize on the cell surface, confirming that the GPI anchor mediates association with specific membrane domains and providing a mechanism for specific signaling. This directed targeting was exploited by coexpressing an external domain-defective protein with a functional protein, both with the CEA GPI anchor. The result was a complete loss of signaling capabilities (through integrin-ECM interaction) and cellular effect (differentiation blockage) of the active protein, which involved an alteration of the size of the microdomains occupied by the active protein. This work clarifies how the GPI anchor can determine protein function, while offering a novel method for its modulation.
Nicholson
Thomas B
TB
McGill Cancer Centre and Biochemistry Department, McGill University, Montréal, Québec, Canada H3G 1Y6.
Stanners
Clifford P
CP
D000818:Animals; D000906:Antibodies / Q000276:immunology; D016466:CHO Cells; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
D000906:Antibodies; D002272:Carcinoembryonic Antigen; D003432:Cross-Linking Reagents; D017261:Glycosylphosphatidylinositols; D016023:Integrins; D050505:Mutant Proteins; D019006:Neural Cell Adhesion Molecules