Sl. Gonias et al., Cytokeratin 8 functions as a major plasminogen receptor in select epithelial and carcinoma cells, FRONT BIOSC, 6, 2001, pp. D1326-D1334
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.