We previously reported the identification and characteristics of hepaCAM, a new immunoglobulin-like adhesion molecule. Frequently lost in diverse tumors, hepaCAM exhibits antiproliferative effects on cancer cells and promotes cell-extracellular matrix (ECM) interactions when re-expressed. Herein, we demonstrate for the first time that hepaCAM is cleaved in the human breast carcinoma MCF7 cells, generating a fragment containing mainly the cytoplasmic domain. The phorbol ester phorbol 12-myristate 13-acetate (PMA) did not affect the cleavage of hepaCAM. However, calcium-influx promoted hepaCAM cleavage independent of PKC. In addition, inhibitors of proteasome and cysteine proteases strongly suppressed the cleavage of hepaCAM, indicating the involvement of proteasome, calpain-1 and cathepsin B. Furthermore, we showed that functions of hepaCAM were impaired when the cytoplasmic domain was cleaved. The truncation mutant of hepaCAM failed to promote cell-ECM adhesion and migration, and lost the inhibitory effects on cell growth, suggesting a regulatory role of the cleavage in hepaCAM functions.

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