Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins

• Published in: Circulation research 2003-06, Vol.92 (12), p.1296-1304
• Main Authors: Lin, Tong, Zeng, Lingfang, Liu, Yi, DeFea, Kathryn, Schwartz, Martin A, Chien, Shu, Shyy, John Y.-J
• Format: Article
• Language: English
• Subjects: Actin Depolymerizing Factors; Actins - metabolism; Animals; Biological and medical sciences; Cattle; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Adhesion; Cells, Cultured; CHO Cells; Cricetinae; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Fundamental and applied biological sciences. Psychology; Heart; Humans; Intracellular Signaling Peptides and Proteins; Lim Kinases; Luciferases - genetics; Luciferases - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microfilament Proteins - metabolism; Microscopy, Fluorescence; Mutation; Plasmids - genetics; Protein Kinases - metabolism; Protein Transport; Protein-Serine-Threonine Kinases - metabolism; Proteins - metabolism; rho GTP-Binding Proteins - metabolism; rho-Associated Kinases; Signal Transduction - physiology; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Stress, Mechanical; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000078780.65824.8B

ABSTRACT—Previous studies have shown that integrin activation and fluid shear stress can modulate the activity of sterol regulatory element binding proteins (SREBPs) in vascular endothelial cells. We investigated the role of small GTPase Rho-mediated signal transduction pathway in this mode of SREBP activation. Fluid shear stress activates the Rho downstream effectors ROCK, LIM kinase (LIMK), and cofilin. The various negative mutants of RhoA, ROCK, LIMK, and cofilin can block the shear stress activation of SREBPs. The shear stress–activated SREBP depends on S2P proteases but not caspase-3. Mechanistically, the endoplasmic reticulum-to-Golgi transport of SREBP cleavage–activating protein requires the actin-based cytoskeleton and is enhanced by the Rho-ROCK-LIMK-cofilin pathway. By enhancing the SREBP-mediated cholesterol metabolism, this unique mechanism may contribute to endothelial cell functions under flow.