Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr

While beta2 integrin ligand-receptor recognition interactions are well char acterized, less is known about how these events trigger signal transduction cascades to regulate the transition from tethering to firm adhesion, sprea ding, and transendothelial migration. We have identified critical positive and negative regulatory components of this cascade in monocytes. Whereas th e Syk tyrosine kinase is essential for beta2 integrin signaling and cell sp reading, the Src family kinase Fgr is a negative regulator of this pathway. Fgr selectively inhibits beta2 but not beta1 integrin signaling and Syk ki nase function via a direct association between the Fgr SH2 domain and Syk t yrosine Y342. The inhibitory effects of Fgr are independent of its kinase a ctivity, are dose dependent, and can be overcome by chemokines and inflamma tory mediators.