A persisting paradox in cytoskeletal regulation of cell motility is the loss of the actin filament fragmenting
protein,
gelsolin, in transformed epithelial cells that have gained the ability to migrate. Either actin filament severing does not occur during motility of
carcinoma cells or a novel fragmentation
protein is expressed during transformation. Using an antibody specific for
severin, the Mr 40,000 actin filament severing
protein from Dictyostelium discoideum amoebae, we have identified a mammalian form of
severin in murine LL/2
carcinoma cells lacking
gelsolin. Mammalian
severin (M-
severin) isolated from LL/2-derived
Lewis lung carcinoma tumors severed
F-actin in a
calcium-dependent manner, mimicking the function of Dictyostelium
severin. M-
severin preferentially localized to the cleavage furrow of dividing LL/2 cells and to the actin-rich cortex of migratory LL/2 cells, known sites of active actin cytoskeleton rearrangement. The mammalian severing
protein was fully expressed in transformed LL/2 epithelial cells but went undetected in normal mouse muscle, liver, spleen, or kidney. Normal mouse lung tissue contained minute amounts of M-
severin, attributed to motile cells in pulmonary connective tissue. In striking contrast to M-
severin,
gelsolin was highly expressed in normal lung but disappeared in transformed LL/2
carcinoma cells. Based on prior observations of a functional role for actin filament fragmentation in cell migration, the simultaneous induction of M-
severin and loss of
gelsolin during epithelial transformation suggests that replacement of
gelsolin by M-
severin may function to achieve actin filament rearrangements necessary for active cell migration in invasive or metastatic
carcinoma. Induction of M-
severin in an invasive
tumor was directly observed in human
colon adenocarcinoma by cytoimmunohistochemistry with
antibodies directed against
severin isolated from both Dictyostelium amoebae and
Lewis lung carcinoma cells. Because normal colon epithelium from the same patient did not express M-
severin, it may serve as a sensitive marker for detection and staging of epithelial
tumors.