The 6 4 Integrin Can Regulate ErbB-3 Expression: Implications for 6 4 Signaling and Function
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.
- SourceAvailable from: Daniela Brina
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- "Integrins affect gene expression also at the level of translation. Adhesion and activation of β 3 - , β 4 - , and β 1 -integrins   led to the translation of specific mRNAs modulating cellular response, both in normal and pathological conditions. Contributing to this scenario, we have previously shown that β1 integrin controls translation during adhesion to fibronectin, through the modulation of the initiation phase. "
ABSTRACT: Adhesion to fibronectin stimulates protein synthesis (translation) of fibroblasts. Protein synthesis stimulation is dependent from the activation of beta(1)-integrin. beta(1)-Integrin elicits a PI3K cascade that modulates eIF4F (eukaryotic initiation factor 4F) complex formation. In the attempt to further dissect elements of the PI3K cascade that might be responsible for fibronectin-stimulated translation, we used pharmacological inhibitors of known kinases. We found that JNK inhibition, by SP600125 treatment, increased (35)S-methionine incorporation. Paradoxically, the increase in methionine incorporation was associated to a reduction of initiation of translation. These data imply that, during the adhesion of fibroblasts to fibronectin, conspicuous protein degradation occurs. Indeed, we found that inhibition of the proteasome by MG132 also increased methionine incorporation. Cotranslational degradation depended on PI3K activation. In spite of this, serum promoted translation, but not cotranslational degradation. The crosstalk between translation and degradation was further analyzed by studying the phosphorylation of initiation factors. Briefly, inhibition of JNK leads to eIF2alpha phosphorylation, which may account for the decrease in initiation of translation. In conclusion, beta(1)-integrin-activated translation causes the synthesis of short-lived proteins, whose degradation is controlled by the JNK pathway. We hypothesize that JNK is a general regulator of cotranslational degradation.Biochimica et Biophysica Acta 03/2010; 1803(7):826-31. DOI:10.1016/j.bbamcr.2010.03.016 · 4.66 Impact Factor
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- "In addition, Guo et al. established that integrin α 6 β 4 may be required for mammary tumourigenesis driven by the expression of ErBB2 (Guo et al. 2006). Folgiero et al. revealed that α 6 β 4 can regulate the expression of ErBB-3 at the level of protein translation, resulting in a signifi cant induction of ErBB-2/ErBB-3 heterodimerization and consequent activation of PI3K (Folgiero et al. 2007; Liu et al. 2007). Introduction of β 4 in β 4 -negative breast carcinoma cells activates signalling from PI3K to Rac (a member of the Rho family of small guanosine triphosphatases) and increases the invasion of these cells in vitro (Shaw, 2001). "
ABSTRACT: Integrins have been reported to mediate cell survival, proliferation, differentiation, and migration programs. For this reason, the past few years have seen an increased interest in the implications of integrin receptors in cancer biology and tumor cell aggression. This review considers the potential role of integrins in cancer and also addresses why integrins are present attractive targets for drug design. It discusses of the several properties of the integrin-based chemotherapeutic agents currently under consideration clinically and provides an insight into cancer drug development using integrin as a target.Perspectives in Medicinal Chemistry 04/2008; 2(2):57-73.
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- "The integrin α6β4 cooperates with growth factor receptors and affects multiple signaling components that contribute to the increased migratory and invasive phenotype of cancer cells    . Among the molecules activated by the integrin α6β4 are PI3-K  and the small GTPase Rac1 . "
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 · 16.72 Impact Factor