The alpha6beta4 integrin can regulate ErbB-3 expression: implications for alpha6beta4 signaling and function.
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.
Folgiero
Valentina
V
Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, Via della Messi d'Oro 156, 00158 Rome, Italy.
Bachelder
Robin E
RE
Bon
Giulia
G
Sacchi
Ada
A
Falcioni
Rita
R
Mercurio
Arthur M
AM
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D004789:Enzyme Activation; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D020890:Neuregulin-1 / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
D039562:Eukaryotic Initiation Factor-4F; D039161:Integrin alpha6beta4; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C087230:heregulin beta1