| First Author | Lebrun P | Year | 2000 |
| Journal | J Biol Chem | Volume | 275 |
| Issue | 49 | Pages | 38371-7 |
| PubMed ID | 10967115 | Mgi Jnum | J:115350 |
| Mgi Id | MGI:3691414 | Doi | 10.1074/jbc.M006162200 |
| Citation | Lebrun P, et al. (2000) Cell adhesion and focal adhesion kinase regulate insulin receptor substrate-1 expression. J Biol Chem 275(49):38371-7 |
| abstractText | Integrins are transmembrane receptors involved in interactions between cells and extracellular matrix proteins. Here we show that cell adhesion regulates insulin receptor substrate-1 (IRS-1) mRNA synthesis. When fibroblasts are held in suspension, lower levels of IRS-1 mRNA, but not of IRS-2 mRNA, are detected, and this effect is due to the negative regulation of IRS-1 transcription rather than to decreased mRNA stability. Upon fibronectin- or vitronectin-mediated integrin stimulation, the level of IRS-1 mRNA was restored within 4 h. The focal adhesion kinase (FAK) is known to be activated upon integrin stimulation, and we found that IRS-1 was not expressed in FAK(-)(/-) cells. Stable re-expression of epitope-tagged FAK in FAK(-)(/-) fibroblasts (DA2 cells) restored normal levels of IRS-1 expression, confirming that IRS-1 mRNA expression is regulated by FAK. It is known that integrins activate the JNK pathway. However, in adherent FAK(-)(/-) cells, we failed to detect activation of JNK, whereas JNK was stimulated in DA2 cells. This confirms the role of FAK in integrin-induced JNK stimulation. FAK-independent stimulation of JNK with anisomycin treatment both in FAK(-)(/-) cells and in suspended FAK(+/+) cells confirmed that IRS-1 mRNA transcription can be partially regulated by JNK. We suggest that integrins can modulate insulin and insulin-like growth factor-1 signaling pathways by regulating the levels of IRS-1 in cells and that FAK-mediated signaling to JNK is one pathway involved in this process. |
