The alpha(6)beta(4) integrin can regulate ErbB-3 expression: Implications for alpha(6)beta(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.
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ABSTRACT: Persistent infection of Mycoplasma hyorhinis (M. hyorhinis) was associated with gastric cancer cell migration and invasion, but the mechanisms were not well understood. Herein, we found that M. hyorhinis activated phosphoinositide 3-kinase (PI3K)-AKT signaling axis in gastric cancer cell lines. Epidermal growth factor receptor (EGFR) was upstream of PI3K-AKT signaling in the context of M. hyorhinis infection, because phosphorylation of AKT Serine 473 was almost completely attenuated by the EGFR inhibitor AG1478 or by EGFR knockdown. Phosphorylation of AKT S473 induced by M. hyorhinis infection was also abolished by PI3K inhibitor wortmannin. Furthermore, we found that p37, a membrane protein of M. hyorhinis, could also promote M. hyorhinis-induced PI3K-AKT signaling activation and cell migration. In addition, pre-treatment with AG1478 or wortmannin significantly inhibited cell migration induced by M. hyorhinis infection or p37 treatment. In conclusion, EGFR-PI3K-AKT signaling plays an important role in M. hyorhinis-promoted cell migration in gastric cancer cells, thus providing a clue to the pathogenesis of M. hyorhinis in gastric cancer.Cancer Cell International 12/2014; 14(1):135. DOI:10.1186/s12935-014-0135-3 · 1.99 Impact Factor
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ABSTRACT: In dairy cows, the extracellular microenvironment varies significantly from the virgin state to lactation. The function of integrin α6β4 is dependent on cell type and extracellular microenvironment, and the precise expression profile of α6β4 and its effects on mammary development remain to be determined. In the present study, real-time PCR and immunohistochemistry were used to analyze the expression and localization of integrin α6β4 in Holstein dairy cow mammary glands. The effects of integrin α6β4 on the proliferation induced by mammogenic mitogens were identified by blocking integrin function in purified dairy cow mammary epithelial cells (DCMECs). The results showed that the localization of β4 subunit and its exclusive partner the α6 subunit were not consistent but were co-localized in basal luminal cells and myoepithelial cells, appearing to prefer the basal surface of the plasma membrane. Moreover, α6 and β4 subunit messenger RNA (mRNA) levels changed throughout the stages of dairy cow mammary development, reflected well by protein levels, and remained higher in the virgin and pregnancy states, with duct/alveolus morphogenesis and active cell proliferation, than during lactation, when growth arrest is essential for mammary epithelial cell differentiation. Finally, the upregulation of integrin expression by both mammogenic growth hormone and insulin-like growth factor-1 and the inhibited growth of DCMECs by function-blocking integrin antibodies confirmed that integrin α6β4 was indeed involved in dairy cow mammary development.In Vitro Cellular & Developmental Biology - Animal 10/2014; DOI:10.1007/s11626-014-9827-1 · 1.00 Impact Factor
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ABSTRACT: Epithelial cells are highly dependent during wound healing and tumorigenesis on the α6β4 integrin and its association with receptor tyrosine kinases. Prior work showed that phosphorylation of the β4 subunit upon matrix engagement depends on the matrix receptor syndecan-1 (Sdc1) engaging the cytoplasmic domain of the β4 integrin and coupling of the integrin to HER2. In this study, HER2-dependent haptotactic migration is compared to chemotactic migration stimulated by EGF. We find that whereas HER2-dependent migration depends on Sdc1, EGF-dependent migration depends on a complex consisting of EGFR, α6β4 and Sdc4. The two syndecans recognize distinct sites at the extreme C-terminus of the β4 integrin cytoplasmic domain. The binding motif in Sdc1 is QEExYx, comprised in part by its syndecan-specific variable (V) region and in part by the second conserved (C2) region that it shares with other syndecans. A cell penetrating peptide containing this sequence competes for HER2-dependent epithelial migration and carcinoma survival, whereas it is without effect on the EGFR-stimulated mechanism. β4 mutants bearing mutations specific for Sdc1 and Sdc4 recognition act as dominant negative mutants to block cell spreading or cell migration that depends on HER2 or EGFR, respectively. The interaction of the α6β4 integrin with the syndecans appears critical for it to be utilized as a signaling platform; migration depends on α3β1 integrin binding to laminin 332, (LN332; also known as laminin 5), whereas antibodies that block α6β4 binding are without effect. These findings indicate that specific syndecan family members are likely to have key roles in α6β4 integrin activation by receptor tyrosine kinases.Journal of Biological Chemistry 09/2014; DOI:10.1074/jbc.M114.586438 · 4.60 Impact Factor