Tetraspanin CD151 regulates RhoA activation and the dynamic stability of carcinoma cell-cell contacts

被引:61
作者
Johnson, Jessica L. [1 ]
Winterwood, Nicole [1 ]
DeMali, Kris A. [2 ]
Stipp, Christopher S. [1 ]
机构
[1] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA
[2] Univ Iowa, Dept Biochem, Carver Coll Med, Iowa City, IA 52242 USA
关键词
Tetraspanin; CD151; E-cadherin; Rho; alpha; 3; beta; 1; integrin; CADHERIN-CATENIN COMPLEX; HUMAN-MELANOMA CELLS; FAMILY GTPASES; BREAST-CANCER; IN-VIVO; INTEGRIN ALPHA-3-BETA-1; METASTASIS SUPPRESSOR; CLINICAL-SIGNIFICANCE; EPITHELIAL-CELLS; PROSTATE-CANCER;
D O I
10.1242/jcs.045997
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 alpha 3 beta 1 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 alpha 3 beta 1 integrin. This could help to explain the phenotypes in human patients and mice lacking CD151.
引用
收藏
页码:2263 / 2273
页数:11
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