Abstract
Anchorage-independent myelomonocytic cells acquire adherence within minutes of differentiation stimuli, such as the proteolytically inactive N-terminal fragment of urokinase binding to its cognate glycosylphosphatidylinositol (GPI)-anchored receptor. Here, we report that urokinase-treated differentiating U937 monocyte-like cells exhibit a rapid and transient inhibition of p56/59(hck) and p55(fgr) whereas no changes in the activity of other Src family kinases, such as p53/56(lyn) and p59(fyn) were observed. U937 transfectants expressing a kinase-defective (Lys267 to Met) p56/59(hck) variant exhibit enhanced adhesiveness and a marked F-actin redistribution in thin protruding structures. Conversely, urokinase as well as expression of wild-type or constitutively active (Tyr499 to Phe) p56/59(hck) stimulates the directional migration of uninduced U937 cells. Accordingly, expression of constitutively active or kinase inactive p56/59(hck) selectively prevents urokinase receptor-dependent induction of either adhesion or motility, indicating that a specific activation state of p56/59(hck) is required for each cell response. In conclusion, modulation of the intracellular p56/59(hck) tyrosine kinase activity switches cell motility towards adherence, providing a mutually exclusive mechanism to regulate these properties during monocyte/macrophage differentiation in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Animals
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Calcitriol / pharmacology
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Cell Adhesion / drug effects
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Cell Differentiation
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Cell Movement* / drug effects
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Cytoskeleton / drug effects
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Enzyme Activation
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Humans
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / enzymology*
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Macrophages / metabolism
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Mice
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / enzymology*
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Monocytes / metabolism
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Mutation
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Phenotype
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Phosphorylation / drug effects
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Protein Kinase Inhibitors
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Protein Kinases / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-hck
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Receptors, Cell Surface / metabolism*
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Receptors, Urokinase Plasminogen Activator
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Temperature
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Transfection
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Transforming Growth Factor beta / pharmacology
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Tumor Cells, Cultured
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Urokinase-Type Plasminogen Activator / metabolism
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Urokinase-Type Plasminogen Activator / pharmacology
Substances
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Actins
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PLAUR protein, human
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Plaur protein, mouse
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, Cell Surface
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Receptors, Urokinase Plasminogen Activator
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Transforming Growth Factor beta
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Protein Kinases
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Protein-Tyrosine Kinases
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HCK protein, human
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Hck protein, mouse
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Proto-Oncogene Proteins c-hck
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Urokinase-Type Plasminogen Activator
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Calcitriol