Urokinase receptor-dependent and -independent p56/59(hck) activation stateis 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-termina l fragment of urokinase binding to its cognate glycosylphosphatidylinositol (GPI)-anchored receptor, Here, we report that urokinase-treated differenti ating U937 monocytelike cells exhibit a rapid and transient inhibition of p 56/59(hck) and p55(fgr) whereas no changes in the activity of other Src fam ily kinases, such as p53/56(lyn) and p59(fyn) were observed. U937 transfect ants expressing a kinase-defective (Lys267 to Met) p56/59(hck) variant exhi bit enhanced adhesiveness and a marked F-actin redistribution in thin protr uding structures. Conversely, urokinase as well as expression of wild-type or constitutively active (Tyr499 to Phe) p56/59(hck) stimulates the directi onal migration of uninduced U937 cells. Accordingly, expression of constitu tively active or kinase inactive p56/59(hck) selectively prevents urokinase receptor-dependent induction of either adhesion or motility, indicating th at a specific activation state of p56/59(hck) is required for each cell res ponse. In conclusion, modulation of the intracellular p56/59(hck) tyrosine kinase activity switches cell motility towards adherence, providing a mutua lly exclusive mechanism to regulate these properties during monocyte/macrop hage differentiation in vivo.