Abstract 3124: Tetraspanin CD151-mediated signaling network between cell-matrix and cell-cell adhesions

Abstract

Abstract CD151 has been suggested to promote cancer invasion and metastasis by regulating adhesion-dependent signaling events through its association with laminin-binding α3β1/α6β1 integrins. Previously, we have demonstrated that homophilic interactions of CD151 stimulate integrin-dependent signaling to c-Jun through the FAK-Src-MAPKs pathways in human melanoma cells. In this study, we found that CD151 plays a role in recruiting Ras, Rac1, and Cdc42, but not Rho, to the membrane region, leading to formation of α3β1/α6β1 integrins-CD151-small GTPases complexes. Adhesion receptor complexes-associated small GTPases were found to be activated by β1 integrins-CD151 complexes-stimulating adhesion events such as interactions of integrins with laminin and homophilic interactions of CD151 on two contacting cells, implicating CD151-mediated signaling network between cell-matrix and cell-cell adhesions. Adhesion-dependent activation of small GTPases appeared to be mediated by the FAK-Src pathways. Meanwhile, EGF and phorbol ester treatment further enhanced CD151-β1 integrin complexes-induced cell motility and MMP-9 expression, along with activation of p38 MAPK and JNK, indicating a positive signaling cross-talk between CD151-β1 integrin adhesion receptor, EGF receptor, and PKC. Using siRNAs and dominant-inhibitory mutant expression constructs for various intracellular signaling mediators, we found that integrin-linked kinase (ILK), PAK1-interacting exchange factor beta (β-PIX), and p21-activated protein kinase 1 (PAK1) were involved in CD151-β1 integrin adhesion receptor complex signaling pathways. Also, MEK3/6 and MEK7 were found to participate in CD151-β1 integrin signaling cascades, upstream of p38 MAPK and JNK, respectively. Taken together, our data strongly suggest that β1 integrin-CD151 adhesion receptor complexes activate c-Jun AP-1 factor via the signaling cascades involving the FAK-Src, ILK-β-Pix, small GTPases-PAK1, MEK3/6-p38 MAPK, and MEK7-JNK pathways, leading to increased cell motility and MMP-9 expression in human melanoma cells. Key words: tetraspanin, CD151, integrin, adhesion receptor, cell signaling Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3124. doi:10.1158/1538-7445.AM2011-3124