Tetraspanin CD151 Stimulates Adhesion-dependent Activation of Ras, Rac, and Cdc42 by Facilitating Molecular Association between β1 Integrins and Small GTPases

Tetraspanin CD151 associates with laminin-binding α3β1/α6β1 integrins in epithelial cells and regulates adhesion-dependent signaling events. We found here that CD151 plays a role in recruiting Ras, Rac1, and Cdc42, but not Rho, to the cell membrane region, leading to the formation of α3β1/α6β1 integrin-CD151-GTPases complexes. Furthermore, cell adhesion to laminin enhanced CD151 association with β1 integrin and, thereby, increased complex formation between the β1 family of integrins and small GTPases, Ras, Rac1, and Cdc42. Adhesion receptor complex-associated small GTPases were activated by CD151-β1 integrin complex-stimulating adhesion events, such as α3β1/α6β1 integrin-activating cell-to-laminin adhesion and homophilic CD151 interaction-generating cell-to-cell adhesion. Additionally, FAK and Src appeared to participate in this adhesion-dependent activation of small GTPases. However, engagement of laminin-binding integrins in CD151-deficient cells or CD151-specific siRNA-transfected cells did not activate these GTPases to the level of cells expressing CD151. Small GTPases activated by engagement of CD151-β1 integrin complexes contributed to CD151-induced cell motility and MMP-9 expression in human melanoma cells. Importantly, among the four tetraspanin proteins that associate with β1 integrin, only CD151 exhibited the ability to facilitate complex formation between the β1 family of integrins and small GTPases and stimulate β1 integrin-dependent activation of small GTPases. These results suggest that CD151 links α3β1/α6β1 integrins to Ras, Rac1, and Cdc42 by promoting the formation of multimolecular complexes in the membrane, which leads to the up-regulation of adhesion-dependent small GTPase activation. Background: CD151 associates with integrins and regulates integrin-dependent small GTPase-mediated cellular behaviors. Results: CD151-expressing cells exhibited increased Ras, Rac, and Cdc42 complexes with integrins and active forms of small GTPases, as compared with CD151-deficient cells. Conclusion: CD151 contributes to integrin signaling to small GTPases by facilitating association of integrins with small GTPases. Significance: Investigating integrin interactions with small GTPases is critical for understanding adhesion signaling.