Urokinase receptor-dependent and -independent p56/59(hck) activation state is a molecular switch between myelomonocytic cell motility and adherence.
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.
Chiaradonna
F
F
International Institute of Genetics and Biophysics, CNR, Via Marconi 10, 80125 Naples.
Fontana
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L
Iavarone
C
C
Carriero
M V
MV
Scholz
G
G
Barone
M V
MV
Stoppelli
M P
MP
D000199:Actins / Q000378:metabolism; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D013696:Temperature; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology
D000199:Actins; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C496631:HCK protein, human; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; D014568:Urokinase-Type Plasminogen Activator; D002117:Calcitriol