Disease relevance of Fgr

• Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr [1].
• These findings suggest that deficiency of Fgr results in a marked reduction of lung eosinophilia and the establishment of a positive feedback loop based on autocrine secretion of eosinophil-active cytokines [2].
• We have now isolated and mapped three overlapping phage clones spanning 33 kb of the murine C-FGR genomic locus [3].

High impact information on Fgr

• These data support a model in which the Src family kinases Hck and Fgr function as negative regulators of myeloid cell chemokine signaling by maintaining the tonic phosphorylation of PIR-B [4].
• Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr [5].
• Fcgamma receptor-mediated phagocytosis in macrophages lacking the Src family tyrosine kinases Hck, Fgr, and Lyn [6].
• We examined FcgammaR signaling and phagocytic function in bone marrow-derived macrophages from mutant mice lacking the major Src family kinases expressed in these cells, Hck, Fgr, and Lyn [6].
• Negative regulation of phagocytosis in murine macrophages by the Src kinase family member, Fgr [7].

Chemical compound and disease context of Fgr

• Using a mouse model of allergic lung inflammation, we found that mice deficient of Fgr, a Src family tyrosine kinase highly expressed in myelomonocytic cells, fail to develop lung eosinophilia in response to repeated challenge with aerosolized OVA [2].

Biological context of Fgr

• Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn [8].
• Although expression of Fgr both in a macrophage cell line and in primary macrophages significantly attenuates ingestion mediated by Fcgamma receptors and CR3, it does not affect macropinocytosis or receptor-mediated endocytosis [7].
• These findings identify a role for Src family kinases in a signaling pathway leading to granule-plasma membrane fusion and suggest that Fgr and Hck would be targets for pharmacological control of adhesion-dependent degranulation in the inflammatory site [9].
• We have deleted the SH2 and SH3 domains from Fyn and Fgr and have generated two point mutations in residues completely conserved in all members of the Src family [10].
• To examine the role of its specific domains in regulating cell migration, we expressed various Fgr molecules in COS-7 cells [11].

Anatomical context of Fgr

• With an immune complex kinase assay in a monocytic leukemia cell line, 2H2 monoclonal antibody was shown to precipitate a 59-kDa protein that corresponds in molecular mass to murine Fgr [12].
• Fgr was expressed highly in lymph nodes, slightly in spleen and peripheral blood leukocytes, and barely in the thymus and was not detected in bone marrow [12].
• In the presence of a mild detergent, Fgr was coimmunoprecipitated with a 70-kDa protein (p70) or with p70 plus several other molecules that were expressed on the cell-surface membrane of macrophage tumor cell lines PU5-1.8 and J774.1, respectively [12].
• We also show that Fgr, like other B cell kinases, is activated in response to cross-linking of the Ag receptor [13].
• We chose Fgr because it is present in high concentrations in circulating phagocytes but is not essential for Fcgamma receptor-mediated ingestion by mouse macrophages [7].

Associations of Fgr with chemical compounds

• These data provide biochemical and morphological evidence that the Src-family kinases Hck and Fgr are required for normal integrin-mediated signal transduction in murine macrophages [14].
• All of these Src family members except Fgr exhibited substantial phosphotyrosine antibody labeling [15].

Regulatory relationships of Fgr

• Crosslinking of Fc gamma RII induced a rapid increase in the tyrosine kinase activity and comodulation of Fgr [16].

Other interactions of Fgr

• However, lung eosinophilia in Fgr-deficient mice correlated with a defective accumulation of GM-CSF and IL-5 in the airways, whereas secretion of these cytokines by spleen cells in response to OVA was normal [2].
• This suggests that exposure of platelets to LDL induces association of apoER2' to Fgr, a kinase that is able to activate p38MAPK [17].
• These results suggest that Fgr is physically and functionally associated with Fc gamma RII and involved in Fc gamma RII-mediated signal transduction pathways [16].
• Additionally, examination of integrin affinity by soluble ICAM-1 binding assays and of beta(2) integrin clustering on the cell surface, showed that integrin activation did not require Hck and Fgr expression [18].
• Mutations in the non-catalytic domains of Fyn and Fgr tyrosine kinases reveal differences in mechanisms of their regulation [10].

Analytical, diagnostic and therapeutic context of Fgr

• Peptide mapping revealed that this kinase activity was derived from Fgr [12].
• We also compared the tyrosine-phosphorylation status of Lck and Fgr to other Src family members in resting platelets using immunoprecipitation and immunoblotting [15].

References