title: Fluid shear stress activation of focal adhesion kinase. Linking to mitogen-activated protein kinases.
abstract: Shear stress, the tangential component of hemodynamic forces, activates the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) signal transduction pathways in cultured vascular endothelial cells to induce the transcriptional activation of many immediate early genes. It appears that integrins, protein-tyrosine kinases, and the structural integrity of actin are important factors involved in these shear stress-induced responses. The underlying molecular events were investigated by the application of a shear stress of 12 dyn/cm2 on bovine aortic endothelial cells (BAEC). We found that such a shear stress increased the tyrosine phosphorylation and the kinase activity of focal adhesion kinase (FAK) and its association with growth factor receptor binding protein 2 (Grb2) in a rapid and transient manner, suggesting that FAK may be linked to these mitogen-activated protein kinase signaling pathways through a Grb2. Son of sevenless (Sos) complex. FAK(F397Y), which encodes a dominant negative mutant of FAK, attenuated the shear stress-induced kinase activity of Myc epitope-tagged ERK2 and hemagglutinin epitope-tagged JNK1. DeltamSos1, encoding a dominant negative mutant of Sos in which the guanine nucleotide exchange domain has been deleted, also attenuated shear stress activation of Myc-ERK2 and hemagglutinin-JNK1. Pretreating the confluent BAEC monolayers with a blocking type anti-vitronectin receptor monoclonal antibody had similar inhibitory effects in these shear stress-activated ERKs and JNKs. Confocal microscopic observation further demonstrated that FAK tended to cluster with vitronectin receptor near the abluminal side of the sheared BAEC. These results demonstrate that FAK signaling is critical in the shear stress-induced dual activation of ERK and JNK.
authors.affiliation: Department of Bioengineering and Institute for Biomedical Engineering, University of California, San Diego, La Jolla, California 92093, USA. shyy@bioeng.ucsd.edu
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Kim
authors.forename: Y L
authors.initials: YL
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Jalali
authors.forename: D D
authors.initials: DD
authors.lastname: Schlaepfer
authors.forename: T
authors.initials: T
authors.lastname: Hunter
authors.forename: S
authors.initials: S
authors.lastname: Chien
authors.forename: J Y
authors.initials: JY
authors.lastname: Shyy
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051380:GRB2 Adaptor Protein; D019833:Genistein / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000502:physiology; D012212:Rheology; D015398:Signal Transduction; D020664:Son of Sevenless Proteins
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D051380:GRB2 Adaptor Protein; D008565:Membrane Proteins; D011506:Proteins; D019030:Receptors, Vitronectin; D020664:Son of Sevenless Proteins; D019000:Phosphotyrosine; D003571:Cytochalasin B; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases