It has previously been reported that shedding of the PTP kappa ectodomain drives enhanced motility of colon cancer cells. Herein, we provide mechanism underlying the regulation of PTP kappa shedding by galectin-3 binding protein. PTP kappa was inarguably scissored by the processed form of proprotein convertase 5 (subtilisin/kexin type 5), and galectin-3 binding protein which is over-produced in colon cancer cells and tissues contributed to increased cancer cell motility by acting as a negative regulator of galectin-3 at the cell surface. The high expression ratio of galectin-3 binding protein to galectin-3 was clinically correlated to lymphatic invasion. These results suggest that galectin-3 binding protein may be a potential therapeutic target for treatment of, at least, colon cancer patients with high expression of galectin-3 binding protein. (C) 2010 Elsevier Inc. All rights reserved.