Tetraspanin CD151 regulates RhoA activation and the dynamic stability of carcinoma cell-cell contacts.
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.
Johnson
Jessica L
JL
Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
Winterwood
Nicole
N
DeMali
Kris A
KA
Stipp
Christopher S
CS
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism; D007365:Intercellular Junctions / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D060185:Tetraspanin 24; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C554715:CD151 protein, human; D015820:Cadherins; C554716:Cd151 protein, mouse; D039201:Integrin alpha3beta1; D011993:Recombinant Fusion Proteins; D060185:Tetraspanin 24; D020742:rhoA GTP-Binding Protein