Targeting plant toxins to the urokinase and alpha 2-macroglobulin receptors.
We have conjugated the ribosome-inactivating protein (RIP) saporin to human urokinase-type plasminogen activator (uPA), and tested the uPA-saporin conjugate for cytotoxicity to uPA receptor-expressing cells. Unlike unconjugated uPA, saporin-conjugated uPA did not require any interaction with plasminogen activator inhibitors to be internalized. We have shown that saporin, as well as other RIPs, binds to the alpha 2-macroglobulin receptor (alpha 2 MR), a cell surface glycoprotein that endocytoses uPA-inhibitor complexes. Thus, the uPA receptor might present uPA saporm to alpha 2MR for internalization of the conjugate, a mechanism similar to that of uPA complexed to specific PA inhibitors. The binding of RIPs to alpha 2MR contrasts with previously proposed non-specific mechanisms for RIP entry into cells. The implications of the interactions between RIPs and alpha 2MR are discussed, with an emphasis on the role of alpha 2MR in mediating RIP immunogenicity and immune suppression.
Cavallaro
U
U
Department of Biological and Technological Research, San Raffaele Scientific Institute, Milano, Italy.
Soria
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MR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001667:Binding, Competitive; D006801:Humans; D007107:Immune System / Q000187:drug effects; D000922:Immunotoxins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000378:metabolism* / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D000922:Immunotoxins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010940:Plant Proteins; D011971:Receptors, Immunologic; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D014568:Urokinase-Type Plasminogen Activator