title: Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression.
abstract: Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-kappaB activation by tumor necrosis factor (TNF)-alpha and enhanced TNF-alpha-mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH(2)-terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab1) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-kappaB activation by TNF-alpha, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-kappaB transcriptional activation by TNF-alpha. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-alpha-induced c-Jun and NF-kappaB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-alpha signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-kappaB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
authors.affiliation: Center for Cardiovascular Research, University of Rochester, Rochester, NY, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Che
authors.forename: Nicole
authors.initials: N
authors.lastname: Lerner-Marmarosh
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Huang
authors.forename: Masaki
authors.initials: M
authors.lastname: Osawa
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohta
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Michael
authors.initials: M
authors.lastname: Glassman
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D004357:Drug Synergism; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D019040:E-Selectin; C098587:GAB1 protein, human; D018836:Inflammation Mediators; D016328:NF-kappa B; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007334:Insulin-Like Growth Factor I; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; C482625:MAP3K3 protein, human