Tetraspanin CD82 has been implicated in
integrin-mediated functions such as cell motility and invasiveness. Although
tetraspanins associate with
integrins, it is unknown if and how CD82 regulates the functionality of
integrins. In this study, we found that Du145
prostate cancer cells underwent morphogenesis on the reconstituted basement membrane
Matrigel to form an anastomosing network of multicellular structures. This process entirely depends on
integrin alpha6, a receptor for
laminin. After CD82 is expressed in Du145 cells, this cellular morphogenesis was abolished, indicating a functional cross-talk between CD82 and alpha6
integrins. Interestingly,
antibodies against other
tetraspanins expressed in Du145 cells such as CD9, CD81, and CD151 did not block this
integrin alpha6-dependent morphogenesis. We further found that CD82 significantly inhibited cell adhesion on
laminin 1. Notably, the level of alpha6
integrins on the cell surface was down-regulated upon CD82 expression, although total cellular alpha6
protein levels remained unchanged in CD82-expressing cells. This down-regulation indicates that the diminished cell adhesiveness of CD82-expressing Du145 cells on
laminin likely resulted from less cell surface expression of alpha6
integrins. As expected, CD82 physically associated with the
integrin alpha6 in Du145-CD82 transfectant cells, suggesting that the formation of the CD82-integrin alpha6 complex reduces
alpha6 integrin cell surface expression. Finally, the internalization of cell surface
integrin alpha6 is significantly enhanced upon CD82 expression. In conclusion, our results indicate that 1) CD82 attenuates
integrin alpha6 signaling during a cellular morphogenic process; 2) the decreased surface expression of alpha6
integrins in CD82-expressing cells is likely responsible for the diminished adhesiveness on
laminin and, subsequently, results in the attenuation of
alpha6 integrin-mediated cellular morphogenesis; and 3) the accelerated internalization of
integrin alpha6 upon CD82 expression correlates with the down-regulation of cell surface
integrin alpha6.