The tetraspanin CD151 regulates cell morphology and intracellular signaling on laminin‐511

Abstract

CD151 (PETA-3 ⁄ SFA-1) is a member of the tetraspanin family of proteins, possessing four membranespanning domains [1]. CD151 was initially identified in platelets [2] and T-cell leukemic cells [3] and has been found to be expressed in a wide variety of cells, including epithelial, endothelial, muscle, Schwann and dendritic cells. Studies using antibodies and small interfering RNA (siRNA) against CD151 have revealed that treatments with these antibodies and siRNA attenuate cell adhesion to and migration on substrates, and disturb epithelial cell-cell adhesion and polarization in cultured cells [4][5][6][7][8][9][10], indicating that CD151 is involved in the regulation of cell-cell and cell-substratum adhesions. Several studies performed in vivo highlight the physiological importance of CD151: in humans, a nonsense mutation in CD151 causes diseases, including end-stage hereditary nephropathy, pretibial epidermolysis bullosa and sensorineural deafness [11]. CD151-null mice show defects in platelet aggregation, keratinocyte migration, T-cell proliferation and pathological angiogenesis, although these mice are viable and fertile [12][13][14][15]. Recently, Sachs et al. [16] reported that CD151 knockout mice show strain-dependent severe renal defects caused by abnormalities of the glomerular basement membrane, loss of podocyte foot processes, glomerulosclerosis and cystic tubular dilation.CD151 interacts with various membrane proteins, including the laminin-binding integrins a3b1, a6b1, a6b4 and a7b1, and other tetraspanin family members, The tetraspanin CD151 forms a stable complex with integrin a3b1, a widely expressed laminin receptor, and is implicated in the regulation of integrin a3b1-mediated cellular responses, including cell attachment, spreading and migration. However, the molecular mechanism by which CD151 regulates integrin a3b1 functions remains unclear. To address this issue, we knocked down CD151 expression in A549 human lung adenocarcinoma cells by RNA interference. When plated on laminin-511 (laminin-10), the CD151-knocked-down cells showed aberrant membrane protrusions and exhibited reductions in the tyrosine phosphorylation of focal adhesion kinase, Src, p130Cas and paxillin. The formation of membrane protrusions was attenuated when the cells were either plated on surfaces coated with higher concentrations of laminin-511 or treated with the integrin b1-activating mAb TS2 ⁄ 16; however, neither treatment could rescue the reduced tyrosine phosphorylation. These results indicate that CD151 knockdown weakens the integrin a3b1-mediated adhesion to laminin-511 and thereby provokes an aberrant morphology, but this reduced adhesive activity is not involved in the decline of signaling events in CD151-knocked-down cells. Thus, our results suggest that CD151 regulates integrin a3b1 functions in two independent aspects: potentiation of integrin a3b1-mediated cell adhesion and promotion of integrin a3b1-stimulated signaling events involving tyrosine phosphorylation.Abbreviations EGFP, enhanced green fluorescent...

Tetraspanins at a glance

“…In general, CD151 only minimally affects adhesion or spreading on matrix proteins to which these integrins bind. Instead, CD151 has been shown to regulate the activation of several signalling molecules downstream of these integrins, including Akt, Src, focal adhesion kinase (FAK), p130CAS (also known as BCAR1), paxillin and Rho family GTPases (Hong et al, 2012;Takeda et al, 2007;Yamada et al, 2008;Yang et al, 2008). Importantly, the influence of CD151 on the activation of these molecules appears to depend on the cellular context, suggesting that CD151 does not function as an adaptor molecule for a particular signalling pathway.…”

Tetraspanins CD9 and CD151 at the immune synapse support T‐cell integrin signaling

“…Tetraspanins modulate downstream integrin signaling, promoting the phosphorylation of FAK, Src, p130CAS, and paxillin [17]. FAK and Src mediate the activation of small GTPases [18], which are associated with tetraspanins [19,20].…”

Roles of tetraspanin proteins in cell and tumor biology

“…These structures were both did not contain elements of the cytoskeleton, and colocalized with MARCKS, which are substrates of PKC that regulates cytoskeleton reorganization during migration (Berditchevski and Odintsova, 1999). In human skin, CD151 was clustered at the basal cell colocalizing with laminin 5 (Lagaudriere-Gesbert et al, 1997; Yamada et al, 2008) connecting focal adhesion with actin filaments as part of hemidesmosomes (Sterk et al, 2000). In polarized epithelial cells, CD9, CD151 and CD81 also localize with cadherins at lateral cell-cell contacts although the effect of antibodies is cadherin-independent.…”