Cytokeratin 8 (K8) is a member of the intermediate filament (IF) gene family expressed by simple epithelial cells and by some
carcinoma cells. The majority of the cellular K8 is assembled with its partner,
K18, into highly insoluble 10 nm filaments that extend from the nucleus to the internal leaflet of the plasma membrane. At desmosomes and hemidesmosomes, K8,
K18, and other IF
proteins are bridged to
proteins with transmembrane domains by a family 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. This may reflect a novel mechanism of
protein penetration through the plasma membrane or binding of secreted K8 to other cell-surface molecules.
Cancer cells are known to secrete K8-containing
protein complexes in vitro and in vivo. These complexes bind
plasminogen as well. The
plasminogen-binding activity of K8 is unique amongst IF
proteins, probably because its sequence includes 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 plasminogen activator (tPA) equivalently. tPA-binding to
K18 may be important in the mechanism whereby K8-K18 complexes promote
plasminogen activation by tPA. Numerous studies have demonstrated correlations between high levels of K8 expression and increased migration and invasion of certain
cancer cells. These 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 demonstrated that certain aggressive
breast cancer cell lines, which have highly activated endogenous
urokinase type-plasminogen activator (uPA)-uPA
receptor (uPAR) systems, do not express high levels of cell-surface K8. The membrane macromolecule that is responsible for
plasminogen-binding and for supporting activation of
plasminogen by uPA on the surfaces of these cell types remains to be determined. This review focuses on the function of K8 as a
plasminogen receptor and its potential role in
cancer.