Cytokeratin 8 functions as a major plasminogen receptor in select epithelial and carcinoma cells

Cytokeratin 8 (K8) is a member of the intermediate filament (IF) gene famil y expressed by simple epithelial cells and by some carcinoma cells. The maj ority of the cellular K8 is assembled with its partner, K18, into highly in soluble 10 nm filaments that extend from the nucleus to the internal leafle t of the plasma membrane. At desmosomes and hemidesmosomes, K8, K18, and ot her IF proteins are bridged to proteins with transmembrane domains by a fam ily of proteins called plakins. K8 does not have a signal peptide or a well -defined transmembrane domain; however, there is substantial evidence that this protein is available to bind plasminogen and K8-specific antibodies on the surfaces of certain epithelial cells in culture, including hepatocytes , hepatocellular carcinoma cells, and various breast cancer cell lines. Thi s may reflect a novel mechanism of protein penetration through the plasma m embrane or binding of secreted K8 to other cell-surface molecules. Cancer c ells are known to secrete K8-containing protein complexes in vitro and in v ivo. These complexes bind plasminogen as well. The plasminogen-binding acti vity of K8 is unique amongst IF proteins, probably because its sequence inc ludes a carboxyl-terminal Lys residue. However, a K8 mutant that lacks the C-terminal Lys still binds plasminogen, albeit with decreased affinity. K18 does not bind plasminogen; however, K8 and K18 bind tissue-type plasminoge n activator (tPA) equivalently. tPA-binding to K18 may be important in the mechanism whereby K8-K18 complexes promote plasminogen activation by tPA. N umerous studies have demonstrated correlations between high levels of K8 ex pression and increased migration and invasion of certain cancer cells. Thes e correlations are most easily explained by the function of IF proteins in determining the rigidity of the cytoskeleton; however, the function of cell -surface K8 as a plasminogen receptor merits consideration. We have demonst rated that certain aggressive breast cancer cell lines, which have highly a ctivated endogenous urokinase type-plasminogen activator (uPA)-uPA receptor (uPAR) systems, do not express high levels of cell-surface K8. The membran e macromolecule that is responsible for plasminogen-binding and for support ing activation of plasminogen by uPA on the surfaces of these cell types re mains to be determined. This review focuses on the function of K8 as a plas minogen receptor and its potential role in cancer.