Article

The alpha(6)beta(4) integrin can regulate ErbB-3 expression: Implications for alpha(6)beta(4) signaling and function

Duke University, Durham, North Carolina, United States
Cancer Research (Impact Factor: 9.28). 03/2007; 67(4):1645-52. DOI: 10.1158/0008-5472.CAN-06-2980
Source: PubMed

ABSTRACT The integrin alpha(6)beta(4) has been shown to facilitate key functions of carcinoma cells, including their ability to migrate, invade, and evade apoptosis. The mechanism involved seems to be a profound effect of alpha(6)beta(4) on specific signaling pathways, especially the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. An intimate relationship between alpha(6)beta(4) and growth factor receptors may explain this effect of alpha(6)beta(4) on signaling. Previously, we showed that alpha(6)beta(4) and ErbB-2 can function synergistically to activate the PI3K/Akt pathway. Given that ErbB-2 can activate PI3K only when it heterodimerizes with other members of the epidermal growth factor receptor family, these data imply that other receptors cooperate in this process. Here, we report that alpha(6)beta(4) can regulate the expression of ErbB-3 using several different models and that the consequent formation of an ErbB-2/ErbB-3 heterodimer promotes the alpha(6)beta(4)-dependent activation of PI3K/Akt and the ability of this integrin to impede apoptosis of carcinoma cells. Our data also support the hypothesis that alpha(6)beta(4) can regulate ErbB-3 expression at the translational level as evidenced by the findings that alpha(6)beta(4) does not increase ErbB-3 mRNA significantly, and that this regulation is both rapamycin sensitive and dependent on eukaryotic translation initiation factor 4E. These findings provide one mechanism to account for the activation of PI3K by alpha(6)beta(4) and they also provide insight into the regulation of ErbB-3 in carcinoma cells.

0 Followers
 · 
103 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The lethality of pancreatic adenocarcinoma stems from an elevated incidence of tumor cell invasion and metastasis that are mediated by mechanisms not yet understood. Recent studies indicate that the proinvasive integrin alpha 6 beta 4 is highly upregulated in pancreatic adenocarcinomas. To assess the importance of this integrin in pancreatic cancer cell migration and invasion, cell lines were screened for integrin alpha 6 beta 4 expression by immunoblotting and fluorescence-activated cell sorting and their ability to migrate and invade toward hepatocyte growth factor (HGF). We found that cell surface expression of the alpha 6 beta 4 integrin correlated with the cells' ability to migrate and invade toward HGF. When cells expressing high levels of integrin alpha 6 beta 4 were treated with small interfering RNA targeting alpha 6 or beta 4 integrin subunits, we observed a reduction in cell migration and invasion. Furthermore, the activity of the small GTPase Rac1 was stimulated by alpha 6 beta 4 integrin expression and was necessary for HGF-stimulated chemotaxis. We discovered that expression of the Rac-specific nucleotide exchange factor, Tiam1 (T-lymphoma invasion and metastasis), was upregulated in cells overexpressing the integrin alpha 6 beta 4 and required for the elevated Rac1 activity in these cells. We conclude that the integrin alpha 6 beta 4 promotes the migratory and invasive phenotype of pancreatic carcinoma cells through the Tiam1-Rac1 pathway in part through the upregulation of Tiam1.
    Neoplasia (New York, N.Y.) 06/2008; 10(5):408-17. · 5.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The lethality of pancreatic adenocarcinoma stems from an elevated incidence of tumor cell invasion and metastasis that are mediated by mechanisms not yet understood. Recent studies indicate that the proinvasive integrin α6β4 is highly upregulated in pancreatic adenocarcinomas. To assess the importance of this integrin in pancreatic cancer cell migration and invasion, cell lines were screened for integrin α6β4 expression by immunoblotting and fluorescence-activated cell sorting and their ability to migrate and invade toward hepatocyte growth factor (HGF). We found that cell surface expression of the α6β4 integrin correlated with the cells’ ability to migrate and invade toward HGF. When cells expressing high levels of integrin α6β4 were treated with small interfering RNA targeting α6 or β4 integrin subunits, we observed a reduction in cell migration and invasion. Furthermore, the activity of the small GTPase Rac1 was stimulated by α6β4 integrin expression and was necessary for HGF-stimulated chemotaxis. We discovered that expression of the Rac-specific nucleotide exchange factor, Tiam1 (T-lymphoma invasion and metastasis), was upregulated in cells overexpressing the integrin α6β4 and required for the elevated Rac1 activity in these cells. We conclude that the integrin α6β4 promotes the migratory and invasive phenotype of pancreatic carcinoma cells through the Tiam1-Rac1 pathway in part through the upregulation of Tiam1.
    Gastroenterology 04/2008; 134(4). DOI:10.1016/S0016-5085(08)62115-0 · 13.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The alpha6beta4 integrin plays a significant role in tumor growth, angiogenesis and metastasis through modulation of growth factor signaling, and is a potentially important therapeutic target. However, alpha6beta4-mediated cell-matrix adhesion is critical in normal keratinocyte attachment, signaling and anchorage to the basement membrane through its interaction with laminin-5, raising potential risks for targeted therapy. Bioengineered Human Skin Equivalent (HSE), which have been shown to mimic their normal and wounded counterparts, have been used here to investigate the consequences of targeting beta4 to establish toxic effects on normal tissue homeostasis and epithelial wound repair. We tested two antibodies directed to different beta4 epitopes, one adhesion-blocking (ASC-8) and one non-adhesion blocking (ASC-3), and determined that these antibodies were appropriately localized to the basal surface of keratinocytes at the basement membrane interface where beta4 is expressed. While normal tissue architecture was not altered, ASC-8 induced a sub-basal split at the basement membrane in non-wounded tissue. In addition, wound closure was significantly inhibited by ASC-8, but not by ASC-3, as the epithelial tongue only covered 40 percent of the wound area at 120 hours post-wounding. These results demonstrate beta4 adhesion-blocking antibodies may have adverse effects on normal tissue, whereas antibodies directed to other epitopes may provide safer alternatives for therapy. Taken together, we conclude that these three-dimensional tissue models provide a biologically relevant platform to identify toxic effects induced by candidate therapeutics, which will allow generation of findings that are more predictive of in vivo responses early in the drug development process.
    PLoS ONE 05/2010; 5(5):e10528. DOI:10.1371/journal.pone.0010528 · 3.53 Impact Factor