MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression.
MEK kinase 1 (MEKK1) has been shown to contribute to the regulation of cell migration, whereas focal adhesion kinase (FAK) is a major player involved in both cell migration and integrin signaling. Here we show that MEKK1 and FAK are co-immunoprecipitated from mouse fibroblasts. Moreover, the association between MEKK1 and FAK appears to be physiologically relevant, as it is enhanced by treatment with epidermal growth factor (EGF). Targeting FAK to the membrane also enhanced its association with MEKK1, indicating that MEKK1 is localized to a membrane-related subcellular domain, perhaps focal adhesions. Interestingly, the expression of insulin receptor substrate-1 (IRS-1) was diminished in MEKK1-deficient fibroblasts, which is similar to an earlier finding in FAK-deficient fibroblasts. Insulin-like growth factor 1 (IGF-1)-induced ERK activation was diminished in MEKK1-deficient cells, but phosphatidylinositol 3-kinase/Akt activation was not. Although integrin reportedly regulates the transcription of the IRS-1 gene via FAK-mediated JNK activation, no impairment of fibronectin-stimulated activation of FAK, ERK, or JNK was observed in MEKK1-deficient cells. Reconstitution of MEKK1 expression restored IRS-1 expression as well as IGF-1-induced ERK activation. Taken together, these findings indicate that MEKK1 interacts with FAK in focal adhesions and regulates IRS-1 expression.
Yujiri
Toshiaki
T
Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Japan. yujirit@yamaguchi-u.ac.jp
Nawata
Ryouhei
R
Takahashi
Toru
T
Sato
Yutaka
Y
Tanizawa
Yukio
Y
Kitamura
Toshio
T
Oka
Yoshitomo
Y
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526295:Irs1 protein, mouse; C496051:Ptk2 protein, mouse; C482578:Map3k1 protein, mouse