Tetraspanins regulate
integrin-dependent
tumor cell interactions with the extracellular matrix. Here we show that
tetraspanin CD151, which plays critical roles in regulating the adhesion and motility of individual
tumor cells, is also an important regulator of collective
tumor cell migration. Near total silencing of CD151 destabilizes
E-cadherin-dependent
carcinoma cell-cell junctions and enhances the collective migration of intact
tumor cell sheets. This effect does not depend on reduced
E-cadherin cell-surface expression or intrinsic adhesivity, or on obvious disruptions in the
E-cadherin regulatory complex. Instead, the loss of CD151 causes excessive RhoA activation, loss of actin organization at cell-cell junctions, and increased actin stress fibers at the basal cell surface. Cell-cell contacts within CD151-silenced monolayers display a nearly threefold increase in remodeling rate and a significant reduction in lifespan as compared to cell-cell contacts within wild-type monolayers. CD151 re-expression restores junctional stability, as does acute treatment of CD151-silenced cells with a cell-permeable RhoA inhibitor. However, a CD151 mutant with impaired association with
alpha3beta1 integrin fails to restore junctional organization. These data reveal that, in addition to its roles in regulating
tumor cell-substrate interactions, CD151 is also an important regulator of the stability of
tumor cell-cell interactions, potentially through its interaction with
alpha3beta1 integrin. This could help to explain the phenotypes in human patients and mice lacking CD151.