Model for cellular pathway of Cbl. (A) Polarized intestinal epithelial cell. The Cbl-intrinsic factor (Cbl-IF) complex is internalized through the cubam receptor for endosome-lysosome processing with subsequent cubam recycling to the cell surface and Cbl release into the cytosol via the LMBD1 lysosomal transporter. Cbl is then either escorted by MMACHC through reduction and activation processing to its destination enzyme partners in the mitochondria and cytosol or is exported through the basolateral membrane by the ATP-dependent MRP1. An as-yet-unknown alternative mechanism for export is also indicated. TC synthesized in the cells is separately secreted in vesicles and becomes available in the plasma for binding of Cbl released via MRP1. (B) Nonpolarized cells. A similar pathway is shown but with TC receptor serving as the entry portal. Professional illustration by Kenneth X. Probst.