| First Author | Iyer V | Year | 2005 |
| Journal | J Cell Sci | Volume | 118 |
| Issue | Pt 6 | Pages | 1185-95 |
| PubMed ID | 15728252 | Mgi Jnum | J:97398 |
| Mgi Id | MGI:3575370 | Doi | 10.1242/jcs.01708 |
| Citation | Iyer V, et al. (2005) Alpha3beta1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: a novel mechanism of integrin-mediated MMP gene expression. J Cell Sci 118(Pt 6):1185-95 |
| abstractText | Matrix metalloproteinases facilitate cell migration and tumor invasion through their ability to proteolyse the extracellular matrix. The laminin-binding integrin alpha3beta1 is expressed at high levels in squamous cell carcinomas and in normal keratinocytes during cutaneous wound healing. We showed previously that alpha3beta1 is required for MMP-9/gelatinase B secretion in immortalized mouse keratinocytes (MK cells) and that this regulation was acquired as part of the immortalized phenotype, suggesting a possible role for alpha3beta1 during malignant conversion. In the current study, we identify a novel mechanism whereby alpha3beta1 regulates the induction of MMP-9 expression that occurs in response to activation of a MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Inhibition of MEK/ERK signaling in wild-type MK cells with a pharmacological inhibitor, U0126, showed that ERK activation was necessary for high levels of endogenous MMP-9 gene expression and activity of a transfected MMP-9 promoter. Furthermore, activation of MEK/ERK signaling in these cells with an oncogenic mutant of Ras, RasV12, increased both endogenous MMP-9 gene expression and MMP-9 promoter activity. Experiments with alpha3beta1-deficient MK cells revealed that alpha3beta1 was required for both baseline levels and RasV12-induced levels of MMP-9 mRNA expression. However, alpha3beta1 was not required for RasV12-mediated activation of ERK or for ERK-dependent MMP-9 promoter activity. Direct comparison of mRNA turnover in the wild type and alpha3-null MK cells identified a requirement for alpha3beta1 in stabilization of MMP-9 mRNA transcripts. These results identify a novel function for integrins in promoting mRNA stability as a mechanism to potentiate MAPK-mediated gene expression. They also suggest a role for alpha3beta1 in maintaining high levels of MMP-9 mRNA expression in response to oncogenic activation of MEK/ERK signaling pathways. |
