Cell adhesion and focal adhesion kinase regulate insulin receptor substrate-1 expression

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. FAR-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 FAR-mediated signaling to JNK is one pathway involved in this process.