Expression and tyrosine phosphorylation of Cbl regulates macrophage chemokinetic and chemotactic movement

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Abstract
Primary macrophages isolated from hck−/−fgr−/− mice display altered morphology and F‐actin cytoskeletal structures and reduced migration. The ability of phorbol myristyl acetate (PMA), a protein kinase C activator that has been reported to increase macrophage spreading and carcinoma cell motility, to rescue these hck−/−fgr−/− defects was tested. Although PMA‐treated wild‐type and hck−/−fgr−/− macrophages exhibited a similar flattened, spread phenotype, PMA did not rescue the hck−/−fgr−/− macrophage migration defect. Instead, both PMA‐treated wild type and hck−/−fgr−/− macrophages were defective in spontaneous and chemotactic migration and tyrosine phosphorylation of the Cbl protooncoprotein was decreased in both. Moreover, c‐cbl−/− macrophages displayed the same impairment of motility as hck−/−fgr−/− macrophages and a similar morphology with less polarization and more dorsal ruffling than wild‐type macrophages. As Hck and Fgr expression and activity were not decreased in c‐cbl−/− macrophages, these results suggest that Cbl is likely to be an important downstream mediator of the Src family kinase‐regulated macrophage motility pathway.