FGR (Gene Name)
FGR is a cytoplasmic protein-tyrosine kinase belonging to the SRC family of protein tyrosine kinases. This kinase was originally described in the context of a feline sarcoma virus isolated from a spontaneous sarcoma of a domestic house cat and named GR-FeSV (Gardner-Rasheed feline sarcoma virus), whose primary translation product was shown to be a 70 kDa gag-fgr fusion peptide (Rasheed et al. 1982). Later studies identified this peptide as having a portion with amino acid homology with actin and another one related to a tyrosine kinase homologous to gene sequences present in the DNA of diverse invertebrate species (Naharro et al. 1983, 1984). FGR is expressed in human and murine hematopoietic cells including granulocytes, monocytes/macrophages, natural killer cells, platelets, and erythrocytes (Berton 2006; Lowell 2004). Its function has been mainly characterized in innate immunity cells and in particular in granulocytes and monocyte/macrophages (Berton et al. 2005; Lowell 2004).
FGR Functions: An Overview
Studies in mice with the genetic deficiency of FGR established the concept that this kinase serves both specific functions and functions emerging from its combined action together with other members of the SRC family of protein tyrosine kinases (SFKs). A paradigm emerged on the role of SFKs in immune cell responses is that they are implicated in activating and inhibitory pathways (Lowell 2011). Consistent with this scenario, FGR deficiency has been reported to result either in defective or enhanced cell responses. In contrast, multiple deficiency of SFKs expressed at the highest level in innate immunity cells, i.e., FGR, HCK and/or LYN, or nonselective inhibition of SFK activities by inhibitory compounds, invariably result in a marked defect in signal transduction and cell activation by different surface receptors.
The immunoreceptors represent a wide family of receptors including antigen receptors expressed by T (TCR) and B lymphocytes (BCR), receptors for the Fc portion of IgE (FcεRs) and IgG (FcγRs), and other ones (Lowell 2004, 2011). Most of them consist of one or more transmembrane proteins implicated in ligand recognition and noncovalently associated homo/heterodimeric signaling adapters such as the FcγR-associated γ chain (FcRγ) or DAP12 (ITAM-Contaning Signal Adaptors). Classical immunoreceptor engagement leads to activation of SFKs, which in turn phosphorylate a tyrosine residue present in the immunoreceptor tyrosine-based activation motif (ITAM) present in the signaling adapters or, in the case of FcγRIIA, in its cytoplasmic tale; phosphorylated ITAMs recruit and activate the tyrosine kinase SYK (Berton 1999; Lowell 2004, 2011). FGR, HCK, LYN and, based on inhibitory studies, other SFKs, have been implicated in macrophage IgG-mediated phagocytosis (Berton 1999; Berton et al. 2005). However, studies with myeloid leukocytes with the sole deficiency of FGR demonstrated that, whereas this kinase is essential for optimal FcγR-dependent phagocytosis in neutrophils, it negatively regulates the phagocytic response in macrophages (Gresham et al. 2000). This inhibitory function involves the immunoreceptor tyrosine-based inhibitory motifs (ITIM)-containing receptor SIRPα which binds the inhibitory tyrosine phosphatase SHP-1 in a FGR-dependent manner. Phosphorylation of tyrosine residues in the ITIM sequence of surface receptors such as FcγRIIB, SIRPα, PIR – B represents the best characterized mechanism of transduction of inhibitory signals by SFKs (Lowell 2004, 2011). Mechanisms underlying a predominant stimulatory or inhibitory effect of the different SFKs, or of one specific SFK like FGR in dependence of the cell context, for example, in neutrophils compared to macrophages (see above), are still unclear (Lowell 2011; Scapini et al. 2009).
Integrins are heterodimeric transmembrane proteins consisting of an α and a β subunit implicated in cell-extracellular matrix or cell–cell interaction. The integrin receptor family includes at least 19 α subunits and 8 β subunits which associate to form at least 25 distinct receptors, several of which are expressed at variable levels in leukocytes. Innate immunity cells express members of the β1, β2, and β3 families and these regulate essential cell responses, including recruitment into inflamed tissues, reactive oxygen intermediate (ROIs) generation, degranulation, cytokine expression and release (Berton and Lowell 1999). Following the demonstration that β2 integrin engagement activates FGR in human neutrophils (Berton et al. 1994), a great deal of information has been accumulated on the role of SFKs in integrin signal transduction in myeloid leukocytes (Abram and Lowell 2009; Berton and Lowell 1999; Berton et al. 2005; Lowell and Berton 1999; Schymeinsky et al. 2007). Studies with mice with the single or multiple genetic deficiency of SFKs established the paradigm that within the integrin signaling pathway FGR appears to work in concert with other SFKs and more specifically to play a redundant role with HCK and, to a minor extent, LYN. The double deficiency of FGR and HCK results in an almost total suppression of several integrin-mediated responses including neutrophil ROI generation and degranulation (Abram and Lowell 2009; Berton et al. 2005; Lowell and Berton 1999; Schymeinsky et al. 2007) and macrophage migration (Baruzzi et al. 2008; Berton et al. 2005). Several components of the myeloid leukocyte integrin signaling pathways that are substrates of FGR/HCK have been identified, including c-CBL, SYK, FAK/PYK2, the p85 subunit of PI3-kinase, cortactin, paxillin SLP-67, and p190RHOGAP (Abram and Lowell 2009; Berton et al. 2005). A direct association of FGR with some of these proteins (c-Cbl, cortactin, SYK, FAK/PYK2) has been reported (Berton 2006).
A major advance in the understanding of integrin signaling in myeloid leukocytes has been the recent demonstration that, similarly to classical immunoreceptors, it involves the ITAM-containing adaptors DAP12 and FcRγ, establishing the paradigm that integrins signal though a SFK/ITAM-containing adaptors/SYK module (Jakus et al. 2007; Lowell 2011).
Signaling by Trimeric G Protein-Coupled Receptors
Several reports implicated SFKs in signal transduction by trimeric G protein-coupled receptors for chemoattractants or chemokines (Berton 1999; Berton et al. 2005; Lowell 2011). Neutrophils deficient of FGR and HCK or FGR, HCK, and LYN, or treated with SFK inhibitors, manifest a marked defect in both superoxide anion generation and degranulation in response to formylated peptides. Similarly, leukocyte responses to several chemokines including CXCL1, CXCL8, CXCL12 and CCL11 were reported to require FGR, HCK, or LYN. However, in analogy with what seen in ITAM/ITIM-containing adaptor-mediated signaling, also within the trimeric G protein-coupled receptor signaling pathway a possible inhibitory role of FGR and HCK in some myeloid leukocyte responses to different chemokines was established (Lowell 2011). Notably, FGR plays a major role in this inhibitory pathway compared to other SFKs and acts via phosphorylation of the ITIM-containing adaptor PIR-B (see Fig. 1 and (Lowell 2011). These contradictory findings may be reconciled emphasizing differences in specific cell responses to trimeric G protein-coupled receptor stimulation. ROIs generation and degranulation seem to require SFKs, whereas activation of integrin adhesiveness and cell migration occur independently of or are even inhibited by SFKs.
E- and P-Selectin-Induced Signaling
The latest advance in the understanding of the role of FGR in regulation of myeloid leukocyte function has been its implication in a signaling pathway triggered by engagement of E- or P-selectin by neutrophil counter-receptors (PSGL-1 and CD44) and regulating β2 integrin LFA-1-dependent slow rolling (Kuwano et al. 2010; Yago et al. 2010; Zarbock and Ley 2009). FGR seems to play a predominant role in the context of this pathway, although, in analogy with other signaling pathways, HCK and LYN are also involved. Notably, the SFK/ITAM-containing adaptors/SYK module identified to be essential for immunoreceptor and integrin signaling is also required for PSGL-1/CD44 signal transduction. Regulation by FGR and other SFKs of selectin-mediated slow rolling represents one of the several mechanisms by which this tyrosine kinase family plays a central role in myeloid leukocyte recruitment into inflammatory sites (Baruzzi et al. 2008; Zarbock and Ley 2009).
FGR and related SFKs have emerged as essential upstream components of several signal transduction pathways regulating myeloid cell responses. Accumulating evidence suggests that several of these pathways share a common module consisting of SFKs, ITAM-containing adaptors and SYK wherein SFKs phosphorylate ITAM tyrosine residues causing binding and activation of SYK. Due to the pleiotropy of SFKs effects, a major challenge of future research is to dissect components of distinct signaling pathways leading to a specific cell response. Additionally, a question that needs to be addressed concerns the mechanisms of activation of SFKs. In fact, although direct or indirect binding to the receptor cytoplasmic tail or codistribution within lipid rafts likely represent a prerequisite for SFK activation, mechanisms responsible for this activation are still elusive. One of the most intriguing aspects of FGR and SFK functions is certainly their capability to activate or inhibit specific cell responses on the basis of their targeting “activation” or “inhibitory” motifs. The balance between these two different actions in the context of a specific SFK or cell function is certainly an issue that deserves more efforts in the future. The present knowledge favors the view that the combined action of different SFKs is essential for activation of a series of cell responses that is critical for the recruitment and activation of myeloid leukocytes into inflammatory sites. If so, it is tempting to speculate that inhibition of this upstream signaling component would tone down responses that are essential for inflammation-based pathologies. Targeting of SFKs as a new strategy to control inflammation is a major challenge for future research.
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