Epidermal growth factor carrier protein binds to cells via a complex with released carried protein nexin

Epidermal growth factor carrier protein (CP) is an arginine endopeptidase bound to epidermal growth factor (EGF) in vivo that processes pro-EGF to EGF and potentiates EGF action. Here, we provide a base for studying the biological functions of CP by showing that highly purified 125I-labeled CP, free of contaminating EGF, is specifically bound and internalized by normal human fibroblasts in serum-free medium. The characteristics of the binding reaction, however, were unusual and not consistent with direct interaction of CP with cell surface receptors. Subsequent experiments showed that cellular binding of 125I-labeled CP was mediated via a cell-secreted protein. We named the protein carrier protein nexin (CPN) because of its close functional similarity to protease nexin, which mediates cellular binding of thrombin or urokinase. Both CPN and protease nexin are secreted by cells, form covalent complexes with regulatory proteases in the extracellular environment, and mediate cellular binding of these proteases, apparently via a cell surface receptor for the nexin moiety of the complex. By several criteria, however, CPN and protease nexin are unique entities. This finding of a specific interaction of a growth factor carrier protein with cells suggests the possibility of additional physiological functions for these carriers in growth factor action or metabolism or both.