Integrins are transmembrane receptors involved in interactions between cell
s and extracellular matrix proteins. Here we show that cell adhesion regula
tes insulin receptor substrate-1 (IRS-1) mRNA synthesis, When fibroblasts a
re held in suspension, lower levels of IRS-1 mRNA, but not of IRS-2 mRNA, a
re detected, and this effect is due to the negative regulation of IRS-1 tra
nscription rather than to decreased mRNA stability. Upon fibronectin- or vi
tronectin-mediated integrin stimulation, the level of IRS-1 mRNA was restor
ed within 4 h, The focal adhesion kinase (FAK) is known to be activated upo
n integrin stimulation, and we found that IRS-1 was not expressed in FAK(-/
-) cells. Stable re-expression of epitope-tagged FAK in FAK(-/-) fibroblast
s (DA2 cells) restored normal levels of IRS-1 expression, confirming that I
RS-1 mRNA expression is regulated by FAK, It is known that integrins activa
te the JNK pathway. However, in adherent FAK(-/-) cells, we failed to detec
t activation of JNK, whereas JNK was stimulated in DA2 cells, This confirms
the role of FAK in integrin-induced JNK stimulation. FAR-independent stimu
lation of JNK with anisomycin treatment both in FAK(-/-) cells and in suspe
nded FAK(-/-) cells confirmed that IRS-1 mRNA transcription can be partiall
y regulated by JNK, We suggest that integrins can modulate insulin and insu
lin-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.