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. 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.
Lebrun
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P
INSERM U145, Institut Federatif de Recherche 50, Avenue de Valombrose, 06107 Nice Cédex 2, France.
Baron
V
V
Hauck
C R
CR
Schlaepfer
D D
DD
Van Obberghen
E
E
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005353:Fibronectins / Q000502:physiology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005786:Gene Expression Regulation; D055504:Insulin Receptor Substrate Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011972:Receptor, Insulin / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection; D019096:Vitronectin / Q000502:physiology
D005353:Fibronectins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019096:Vitronectin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases