Abstract
Blood flow can modulate vascular cell functions. We studied interactions between integrins and Flk-1 in transducing the mechanical shear stress due to flow. This application of a step shear stress caused Flk-1. Casitas B-lineage lymphoma (Cbl) activation (Flk-1. Cbl association, tyrosine phosphorylation of the Cbl-bound Flk-1, and tyrosine phosphorylation of Cbl) in bovine aortic endothelial cells (BAECs). The activation of integrins by plating BAECs on vitronectin or fibronectin also induced this Flk-1. Cbl activation. The shear-induced Flk-1. Cbl activation was blocked by inhibitory antibodies for alphavbeta3- or beta1-integrin, suggesting that it is mediated by integrins. Inhibition of Flk-1 by SU1498 also abolished this shear-induced Flk-1. Cbl activation. In contrast to the requirement of integrins for Flk-1. Cbl activation, the Flk-1 blocker SU1498 had no detectable effect on the shear-induced integrin activation, suggesting that integrins and Flk-1 play sequential roles in the signal transduction hierarchy induced by shear stress. Integrins are essential for the mechanical activation of Flk-1 by shear stress but not for the chemical activation of Flk-1 by VEGF.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Animals
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Aorta / cytology
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Cattle
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Cells, Cultured
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Endothelial Growth Factors / pharmacology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism*
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Integrin beta1 / metabolism*
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Intercellular Signaling Peptides and Proteins / pharmacology
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Ligands
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Lymphokines / pharmacology
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Lymphoma, B-Cell
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Oncogene Protein v-cbl
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Phosphorylation
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Proteins / metabolism
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Receptors, Vitronectin / metabolism*
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Retroviridae Proteins, Oncogenic / metabolism
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Shc Signaling Adaptor Proteins
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Stress, Mechanical
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Tyrosine / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
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Vascular Endothelial Growth Factors
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Endothelial Growth Factors
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Integrin beta1
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Intercellular Signaling Peptides and Proteins
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Ligands
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Lymphokines
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Oncogene Protein v-cbl
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Proteins
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Receptors, Vitronectin
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Retroviridae Proteins, Oncogenic
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Shc Signaling Adaptor Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Tyrosine
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Vascular Endothelial Growth Factor Receptor-2