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(Journal of Leukocyte Biology. 2000;68:603-613.)
© 2000 by Society for Leukocyte Biology

Src kinase-mediated signaling in leukocytes

Zeljka Korade-Mirnics and Seth J. Corey

Department of Pediatrics and Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania

Correspondence: Seth J. Corey, M.D., Division of Hematology-Oncology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail: scorey{at}pitt.edu


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ABSTRACT
 
A concert of antigens, antibodies, cytokines, adhesion molecules, lipid factors, and their different receptors mediate leukocyte development and inflammatory responses. Regardless of the stimulus and receptor type, members of the Src family of protein tyrosine kinases (PTKs) play a critical role in initiating the numerous intracellular signaling pathways. Recruited and activated by the receptor, these Src PTKs amplify and diversify the signal. Multiple pathways arise, which affect cell migration, adhesion, phagocytosis, cell cycle, and cell survival. Essential nonredundant properties of Src PTKs have been identified through the use of gene targeting in mice or in the somatic cell line DT40. Because of their role in mediating leukocyte proliferation and activation, Src PTKs serve as excellent drug targets. Inhibitors of Src family members and dependent pathways may be useful in the treatment of human diseases similar to drugs known to inhibit other signal transduction pathways.

Key Words: signal transduction • leukocytes


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LEUKOCYTE SIGNAL TRANSDUCTION
 
Lymphocytes and phagocytes protect the body against infection and excessive inflammation. To perform these functions, leukocytes must sense infection or inflammation, migrate to and anchor at the involved site, ingest and destroy the infectious agent, and clean up the detritus. No single type of leukocyte can perform all of these functions. Different leukocyte cells must interact and coordinate their activities with other types and accessories such as endothelial cells and fibroblasts. Peptides in the form of antibodies and cytokines, lipid mediators, extracellular matrix, and reactive oxygen species provide signals for this concert of infection control and inflammation. Receptors, primarily on the cell surface of leukocytes, receive these signals and process them via second messengers or cascades of pathways. As a result of this process of signal transduction, neutrophils, eosinophils, monocytes/macrophages, T cell lymphocytes, or B cell lymphocytes produce inflammation.

Leukocytes develop, differentiate, and expand by growth factors and cytokines operating on their cognate receptors, which either contain intrinsic enzymatic activity or recruit an enzyme(s) from the cytosol. They sense chemoattractant gradients via seven-transmembrane, G protein-coupled receptors (GPCR). Leukocytes attach to other cells or extracellular matrix via the integrins. Antigen is presented or antibody is retained by leukocytes via multimeric receptors. Typically present on any particular leukocyte, five different classes of receptors may be sequentially or concurrently activated [1 2 3 4 5 6 ]. One more common theme is that each receptor class utilizes a member of the Src family of protein tyrosine kinases (PTKs) as a secondary effector (Fig. 1 and Table 1 ).



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  		Figure 1. Src Participates in the signal transduction through different receptor types. There are five different types of receptors: receptors with encoded effector domains (RTK), G protein-coupled receptors (GPCR), receptors for adhesion molecules (integrins), hematopoietin/cytokine receptors (H/CR), and multimeric receptors. Effector enzymes commonly use serine/threonine or tyrosine kinases. TK, tyrosine kinase domain is shown for the RTK.


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  		Table 1. Src PTK Activation by a Variety of Cytokine and Immune Receptors

Src family members are non-receptor PTKs, which are expressed in a variety of hematopoietic and non-hematopoietic tissues (Table 2 ) [7 ]. Usually multiple members are expressed in the same cell or tissue. They participate in a variety of cellular processes: cytoskeletal assembly and organization, cell-cell contact, cell-matrix adhesion, induction of DNA synthesis, cell survival, and cellular proliferation [7 ]. Better understood in terms of their mechanisms of activation than their function, Src PTK is regulated by posttranslational phosphorylation and dephosphorylation [8 ]. Src kinases are also regulated by ubiquitin-mediated proteolysis [8 ].


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  		Table 2. Distribution of Src PTK in Hematopoeitic Tissues

So critical to a wide range of cellular behavior, protein tyrosine phosphorylation was first described in studies on Src, just 20 years ago [9 ]. Studies on Src led to the identification of receptor-encoded tyrosine kinases, signaling domains in a wide range of molecules, and signaling complexes in a variety of subcellular compartments. More recent insights into the regulation of Src, identification of more Src substrates, binding partners, and signaling cascades, and therapeutic inhibition of PTKs prompt this review of Src-related PTKs in leukocyte biology [for other recent reviews, see refs. 10 11 12 13 ]. In this review, we will highlight the roles played by Src PTKs in development, adhesion, phagocytosis, and survival in both lymphocytes and myeloid cells. In sum, Src PTKs play a general role in initiation and propagation of signals generated by a variety of different receptor types.


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SRC FAMILY MEMBERS
 
Members of Src family kinases found in mammalian cells are Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, B cell lymphocyte kinase (Blk), and Yrk [11 , 14 15 16 17 18 19 20 21 ]. Src’s importance was first recognized as the retroviral oncogene that transformed chicken fibroblasts, causing sarcomas [22 ]. Yet, of the other Src PTKs, only c-Yes and c-Fgr have a retroviral oncogene form. Src, Yes, Fyn, and Lyn are widely distributed throughout the organism, whereas Lck, Fgr, Hck, and Blk are confined to lymphoid and myeloid tissues [23 ]. Several of the Src PTKs, Fyn, Lyn, and Hck, occur in alternatively spliced isoforms [24 25 26 27 28 29 ]. The physiological significance of these isoforms and the redundancy of Src PTKs remain elusive. Although the Src PTKs are found mainly in association with the cell membrane and with other signaling molecules, they may be found in other cellular compartments [30 ]. Src, Fgr, and Lyn may be nuclear [23 , 31 32 33 ], Hck is cytoplasmic [34 ], Lck is on the plasma membrane and pericentriolar vesicles in T lymphocytes, and Fyn is on centrosomes and microtubule bundles [35 ]. The role of Src PTKs in specific subcellular association is suggested by the compartmentalized availability of substrates and binding partners. The functional significance of different Src PTKs in different compartments is not well understood.


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STRUCTURAL FEATURES OF SRC PTKs
 
Src PTKs share structural motifs, which are essential for their function (Fig. 2 ). Some of these structural motifs may be found in a wide range of signaling molecules, including other non-receptor PTK (comparison of motifs may be found in Table 3 ). At the amino terminus of the Src PTK, the Gly (position 2) and Cys (position 3) residues provide an acceptor site for the addition of myristate and/or palmitate [36 , 37 ]. This posttranslational modification promotes protein association with the lipid membrane (all of the Src PTKs are found at the inner surface of the cell membrane). For Src and Blk, no palmitoylation occurs, and it is unclear what this absence means. Membrane insertion via fatty acid acylation is required for transformation by v-Src [38 ]. In addition to bringing Src PTKs physically close to receptors and integral membrane proteins, this acylation permits them to localize to a subdomain of the cell membrane, known as the lipid raft [39 , 40 ]. These lipid rafts have a high cholesterol and glycolipid content and are enriched with signaling molecules and glycosylphosphatidylinositol (GPI)-linked proteins [41 ]. GPI-linked proteins include CD14, CD16b, CD24, CD48, CD52, CD55, CD58, CD59, CD66b, CD66c, CD67, CD73, CD87, CD157, and Thy-1. Most of these proteins co-precipitate with Src PTKs, and their cross-linking results in tyrosine phosphorylation events [42 , 43 ]. In sum, Src PTKs localize to and contribute to membrane-cytosol areas of high signaling activity. The least understood component of Src PTKs is their unique domain, the amino-terminal ~60 amino acids that confer specificity. In Lck this unique domain provides a motif to interact with CD4 or CD8 [44 ]. In the same cell, Fyn associates with the T cell receptor [45 ].



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  		Figure 2. Structural and functional domains of Src. (A) Src consists of four major domains: the unique region, the SH3 domain, the SH2 domain, and the catalytic or SH1 domain. The unique region contains a conserved motif for fatty acylation, which is uncommonly referred to as the SH4 domain. The carboxy-terminal portion of the SH1 domains has the critical negative tyrosine phosphorylation site. The tyrosine residue in the catalytic domain that serves as a positive regulatory site is not shown. (B) Src PTK activity is negatively regulated by two intra-molecular associations. The SH3 domain recognizes a poly-proline helix motif at the SH2-SH1 juncture. The SH2 domain recognizes a carboxy-terminal phosphotyrosine residue. A phosphatase, e.g., CD45, hydrolyzes that phosphotyrosine, which results in change in physical conformation and catalytic activity.


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  		Table 3. Structural Components of Non-Receptor Protein Tyrosine Kinase Families

The next key feature of Src PTKs is the presence of two domains, which facilitate protein-protein interactions. Because these two domains were first appreciated in Src PTK and then found in a wide variety of signaling molecules, they have merited the labels SH for Src homology. The SH3 domain consists of 40–70 amino acid residues and recognizes proline-rich motifs (PRM) [46 47 48 ]. These PRMs are vaguely characterized as RXPXXP or PXXP, where R is arginine, P is proline, and X is any amino acid. The solving of the SH3 domain by crystallography and nuclear magnetic resonance spectroscopy reveals a "clasped hands" interaction, whereby the PRM assumes a particular helical appearance (poly-proline helix II) and interdigitates with pockets and a salt bridge in the SH3 domain. Surprisingly, a poly-proline helix II is found in Src itself at the beginning of the catalytic domain. This intrinsic SH3-proline interaction is one of two key mechanisms, which negatively regulates Src kinase activity. Although the SH3-PRM interaction is weak, with an apparent binding affinity in µM, this interaction may be important to capture substrates for Src PTKs. It is interesting that the affinity of SH3 domains for HIV Nef in vitro does not predict kinase activation by Nef in vivo [49 , 50 ]. In coexpression experiments in Rat-2 fibroblasts, association of Nef and Hck leads to kinase activation both in vitro and in vivo. Coexpression of Nef with Lyn was without effect, although Nef shows equivalent binding to full-length Lyn and Hck.

The SH2 domain typically consists of 100 amino acids and binds with high affinity to specific phosphotyrosine motifs [46 , 51 ]. The SH2 domains and their cognate phosphotyrosine motifs are found in a number of signaling molecules. Yet, only 0.01% of total cell proteins are tyrosine phosphorylated, and not all of the phosphotyrosine residues serve as a docking site for SH2-containing proteins. The apparent affinity for an SH2 domain to its cognate phosphotyrosine motif is in nM. Through an ingenious method of affinity chromatography, Cantley and co-workers determined the alphabet code, or "zip code" of SH2 recognition [52 ]. The three amino acids, carboxy-terminal to the phosphotyrosine, determine the specificity. Src PTKs bind phosphotyrosine in the context of YEEI, this is the optimal binding sequence. Like Src’s intrinsic SH3-PRM interaction, there is an intrinsic SH2-phosphotyrosine interaction that negatively regulates Src kinase activity. It is this critical phosphotyrosine that is mutated in v-Src and results in the constitutively active form of Src [53 ].

The SH1 domain constitutes the catalytic domain, which comprises the carboxy-terminal ~250 amino acids [54 ]. Within the catalytic domain are the positive autophosphorylation site (for Src, Tyr 416) and the negative phosphorylation site (for Src, Tyr 527). The Csk (carboxy-terminal Src kinase) and its related Chk (Csk homologous kinase) phosphorylate that tyrosine site [55 , 56 ]. It is interesting that no significant abnormalities were found in Chk/Hyl mutant mice [57 ], however, Csk-deficient mice died during embryogenesis with severe neural tube defects [58 , 59 ]. Chk/Hyl did not affect the activity of Src, Hck, and Fgr in cultured bone marrow cells [57 ]. The newly described membrane protein, Cbp (Csk binding partner) recruits Csk to the lipid raft, and thus facilitates the tyrosine phosphorylation of Src [60 ]. How Cbp becomes active is another mechanism, awaiting elucidation.


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SRC SUBSTRATES AND BINDING PARTNERS
 
Many stimuli lead to the increased kinase activity of Src PTKs via a variety of receptor types. These stimuli also lead to activation of other PTKs, some of which may be downstream of Src (e.g., Btk or Syk) and some may be independent of Src (e.g., Jak or receptor PTKs). The substrate phosphorylation is guaranteed by activation of multiple PTKs or by activation of specific PTK and its site-specific tyrosine phosphorylation. Several biochemical features may predict whether a protein may be Src substrate, with ultimate identification of a bona fide Src substrate resting on the absence (near absence) of phosphorylation in Src PTK-deficient cell line or tissue. Substrates should be found in the subcellular locations where Src may be found, e.g., proximate to the plasma membrane. Substrates may have a proline-rich region, which serves as a docking site for the Src SH3 domain. Substrates may also be tyrosine phosphorylated and require additional tyrosine phosphorylation mediated by Src. In that case, substrate availability may be directed via Src SH2/phosphotyrosine interaction. Although there does not appear to be a highly specific Src SH3 PRM, there is one for Src SH2 domain. The preferred Src SH2 binding motif is YEEI/L, where the Tyr is phosphorylated. In addition, the Src substrate is characterized by a Tyr residue found within the highly acidic milieu provided by repeated Asp or Glu residues. Src-like PTKs may have a requirement for Ile or Leu in the position -1 with respect to the phosphorylated tyrosine residue in position 0. Blk and Lyn have a strong preference for a negatively charged amino acid in position +1, but Src prefers Trp or Gly in this position [61 ]. To date, the main substrates of Src PTKs are adaptor molecules [Cbl, Crk, p85 subunit of phosphatidylinositol 3-kinsase (PI 3-kinase), Shc, Vav], cytoskeletal proteins (annexin II, ß- and {gamma}-catenin, paxillin, talin, vinculin, cortactin, AFAP110), enzymes [focal adhesion kinase (FAK), Tec, phospholipase C{gamma} (PLC{gamma}), mitogen activated protein (MAP) kinase, Ras-Gap], and nucleotide binding proteins [signal transducer and transcriptional activator (STAT), Tcf, Sam68] [11 ].


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EXPERIMENTAL APPROACHES TO DECIPHER SRC PTKs PATHWAYS
 
It has been a challenge to assign a specific function to a particular Src PTK because of their redundancy in tissue expression and commonality in signaling pathways activated by a variety of stimuli. Much of what we believe is conjectural and contextual. One key approach is to study the effects of gene deletion in either mutagenized cell or in the whole organism (mouse knockouts).

The chicken DT40 B cell line has been widely appreciated; it is an example of successful use of a cell line for somatic cell knockout experiments [62 ]. The DT40 cell line was derived from a bursal lymphoma caused by infection from the avian leukosis virus and subsequent deregulation of c-Myc [63 ]. It is interesting that this cell line undergoes homologous recombination at a high frequency, so it has been used by a variety of investigators to study the effects of somatic cell gene targeting. The DT40 cell line expresses only one Src PTK (i.e., Lyn), making it highly relevant to investigators of B cell receptor and Src signaling. We have modified this cell line to analyze the Lyn PTK contribution to cytokine [granulocyte colony-stimulating factor (G-CSF)] receptor signaling [64 ].

Most of what we believe to be specific features of Src PTKs has come from mouse knockouts [23 ]. Some of the results have been surprising, even disappointing. Yes and Blk knockout mice are normal [65 , 66 ]. Hck-deficient or Fgr-deficient mice have a few subtle myeloid cell deficiencies [67 , 68 ]. The knockout of Src causes osteopetrosis and impaired bone remodeling, which was unpredictable [69 ]. Other Src PTKs gene targeting has resulted in mice with abnormal lymphoid development (described below). A greater role for Src PTKs has been appreciated when investigators created double or triple knockouts. For instance, the Src/Yes and Src/Fyn double knockouts are lethal [65 ], the Hck/Fgr double knockout has compromised host defense [68 , 70 ], and Btk/Lyn double knockouts have a more severe immunodeficiency than Btk knockout mice [65 , 67 ]. Two-thirds of Hck-/- Src-/- double mutants die at birth; surviving animals develop a severe form of osteopetrosis and show extreme levels of splenic extramedullary hematopoiesis, anemia, and leukopenia [71 ]. These hematopoietic defects are caused by abnormalities in the bone marrow environment because Hck-/- Src-/- mutant stem cells reconstitute a normal hematopoietic system in irradiated wild-type mice. Fgr-/- Src-/- double mutants have no defects beyond those observed in Src-/- animals. Fgr and Hck levels are increased in Src-/- osteoclasts. Hck and Src serve partially overlapping functions in osteoclasts, and the expression of Hck in Src-deficient osteoclasts ameliorates their functional defects.

It is surprising to note that Hck-/-Fgr-/-Lyn-/- mice are moderately healthy and fertile. However, the total protein phosphotyrosine level is greatly reduced in macrophages derived from these mice. These cultured macrophages express normal levels of CD14 and no other Src-family kinases were detected. The analysis of both elicited peritoneal macrophages (PEMs) and bone marrow-derived macrophages (BMDMs) from triple-mutant mice shows lack of defects in lipopolysaccharide (LPS)-induced activation. Nitrite production and cytokine secretion [interleukin (IL)-1, IL-6, and tumor necrosis factor {alpha} (TNF-{alpha})] are normal or even enhanced in Hck-/-Fgr-/-Lyn-/- macrophages after LPS stimulation. The development of tumor cell cytotoxicity is normal in triple-mutant BMDMs and only partially impaired in PEMs after LPS stimulation. The activation of the ERK1/2 and JNK kinases, as well as the transcription factor NF-{kappa}B, are the same in normal and mutant macrophages after LPS stimulation [72 ].


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SRC PTKs IN MEDIATING LEUKOCYTE DEVELOPMENT: T CELL RECEPTOR (TCR) AS A PARADIGM
 
The TCR consists of two subunits, most commonly the {alpha} and ß chains. TCR forms complexes with accessory molecules such as the {gamma} and {zeta} chains and receptors such as CD3, CD4, or CD8 [73 ]. Antigen activation of the TCR rapidly induces changes in protein tyrosine phosphorylation of the immunoreceptor tyrosine activation motif (ITAMS) found in the {zeta}- and CD3-associated chains (schematized in Fig. 3 ) [45 , 74 , 75 ]. The initial events involve the activation of CD45 and its subsequent hydrolysis of the carboxy-terminal phosphotyrosine of Fyn. Amplifying the signal of the cross-linked TCR, Fyn then proceeds to phosphorylate the ITAMS, which serve as docking sites for the tandem SH2 domains of zeta-associated protein kinase-70 kDa (ZAP-70). Among the diverse signaling events is the activation of PLC{gamma}, which leads to hydrolysis of phosphatidylinositol-4,5-bisphosphate and the production of diacylglycerol and inositol trisphosphate. Diacylglycerol activates protein kinase C (PKC), and inositol trisphosphate releases intracellular calcium from the endoplasmic reticulum. Additional molecules are recruited and different pathways activated, such as PI 3-kinase through Cbl, growth receptor binding partner 2 (Grb2)-Sos-Ras through p36 adaptor molecule and/or Shc (Fig. 4 ), and Jun amino-terminal kinase (JNK) through Vav-Rac. Cellular responses include cell cycle progression and gene transcription.



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  		Figure 3. Activation of multimeric receptors. (A) For multimeric receptors, like TCR, BCR, and the FcR, CD45 hydrolyzes the carboxy-terminal phosphotyrosine of a Src PTK (1), e.g., Fyn, which in turn phosphorylates the tandem Tyr residues comprising an ITAM (2). (B) The phosphotyrosine residues serve as a docking site for the tandem SH2-containing ZAP-70 or Syk (3). Binding of the ZAP-70 (or Syk) to the ITAM results in its activation. (C) One of ZAP-70’s important substrates is PLC{gamma}, which then acts on phosphatidylinositol-4,5-bisphosphate to generate diglyceride and inositol trisphosphate (4), an example of cross-talk between tyrosine phosphorylation and PKC/Ca2+ signaling networks.



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  		Figure 4. Src-Shc-Grb2-Ras-MAP kinase pathway. One important signaling pathway controls proliferation. Src phosphorylates the adaptor molecule Shc, which recruits Grb2 and the Ras exchange factor Sos. In turn, Ras becomes activated, triggering the serine kinase cascade that includes MAP kinase kinase, MAP kinase, and additional serine kinases, such as p90Rsk. Src can also bypass Ras and activate Raf directly.

Lck and Fyn have non-redundant roles in T cell function: whereas Lck associates with CD4 and CD8 integral membrane proteins, Fyn associates with TCR [45 ]. Lck is expressed in pre-TCR thymocytes and Fyn is expressed in mature thymocytes [76 ]. Although T cell leukemia has been described with constitutive activation of Lck, neither Lck nor Fyn have been found defective in patients with T cell immunodeficiency. The Lck knockout causes a T cell maturation defect [77 78 79 ]. The Fyn knockout causes defective TCR signaling [80 , 81 ]. Lck-deficient mice have dramatic effect on T cell development, whereas Fyn-deficient mice have a subtle defect.

Normal B cell development is regulated by other Src PTKs [82 , 83 ]. Blk (B lymphocyte kinase) is expressed in B cell lineage and has a role in the B cell proliferation. Transgenic mice expressing constitutively activated Blk (Y495F) show malignant transformation in the B lymphoid progenitors characteristic of proB/preB-I to preB-II transition [84 ]. Expression of constitutively active Blk in the T cells gave rise to clonal, thymic lymphomas composed of intermediate single-positive cells. The Lyn-deficient mice develop a lupus-like syndrome. They have reduced number of peripheral B cells, lack the response to B cell receptor (BCR) cross-linking or LPS activation, and with age mice develop high serum IgM levels, lymphadenopathy, and splenomegaly [85 , 86 ]. Playing a role comparable to Lck and Fyn in T cells, Lyn promotes normal B cell development, including deletion of autoreactive clones, and BCR function.

The role for Src PTKs in myeloid cell development is less clear, but they do play a role in promoting growth factor-induced cell cycle progression. Multiple studies show that Src PTKs amplify the proliferative signals generated by RTK such as platelet-derived growth factor receptor or the macrophage colony-stimulating factor receptor [87 88 89 ]. We have recently reported that the presence of Lyn was required for G-CSF-induced proliferation in hematopoietic cells [64 ]. Subsequent studies identified Cbl and Shc as two Lyn substrates, which were critical for proliferation [90 ]. Treatment with stem cell factor (SCF) leads to an association of Lyn with the juxtamembrane region of its cognate receptor, c-Kit, and an increase in Lyn activity [91 , 92 ]. Application of Lyn antisense oligonucleotides or PP1, an inhibitor, results in dramatic inhibition of SCF-induced proliferation of hematopoietic cells. Src kinases may also contribute to differentiation of myeloid cells. Expression of activated hematopoietic cell kinase (Hck) blocked granulocytic differentiation of 32Dcl3 cells in response to G-CSF. These results suggest that up-regulation of Hck expression is not required for granulocytic differentiation [93 ]. During urokinase-induced differentiation of U937 cells, there is rapid and transient inhibition of Hck and Fgr kinase activity and no change in Fyn or Lyn activity [94 ].


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SRC PTKs IN LEUKOCYTE ADHESION AND MIGRATION: INTEGRIN AS A PARADIGM
 
Neutrophils adhere to the vascular endothelium, migrate through the vascular basement membrane, and accumulate at the involved site. Monocytes/macrophage and lymphocytes also migrate and adhere [95 , 96 ]. Adhesion, migration, and accumulation comprise a multi-step process mediated by the interaction of a number of adhesion receptors on leukocytes and ligands expressed on the other leukocytes and endothelial tissue: selectins, gangliosides, integrins, and cell adhesion molecules [97 , 98 ]. In terms of intracellular signaling, the best-understood interaction is that mediated by the integrin receptors expressed on the neutrophils and platelets [99 , 100 ]. The functional integrin receptor is a dimer of {alpha} and ß subunits. There are 22 different integrin receptors made up through combination of 17 different {alpha} and 8 different ß subunits [101 ]. The very complex nature of integrin receptors has been reviewed [100 , 102 ]. Cross-linking of integrin receptors in leukocytes induces adhesion, release of specific granules and mediators, and up-regulation of proinflammatory cytokines. Engagement of integrin receptors causes clustering and quickly triggers changes in tyrosine phosphorylation of the {alpha} and ß subunits themselves and cytoskeletal-associated proteins (see Fig. 5 ) [103 ]. These include: FAK, paxillin, tensin, and cortactin. Other molecules that regulate cytoskeletal changes are phosphorylated: Cbl, Cas, and Vav. Integrin receptor complex recruits FAK directly through its ß subunit and/or through its proximity to paxillin and tensin. FAK undergoes autophosphorylation at Tyr397, which then serves as a docking site for Src SH2. Src is then responsible for amplifying FAK’s signal, and it is likely to be the PTK that phosphorylates paxillin, tensin, Cbl, and Cas. One of the substrates for Src is also FAK at Tyr925. This phosphotyrosine site serves as a binding site for Grb2. FAK can itself associate with and activate PI 3-kinase, or Src can perform the same function via Cbl. Thus, integrin signaling nicely describes the amplifying and diversifying effects of Src that result in a network of events. Besides causing adhesion via formation of focal contacts, this integrin-FAK-Src cascade induces changes in anchorage independence, cell shape, cell cycle progression, and gene transcription [104 105 106 ].



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  		Figure 5. Src-Fak-paxillin complex. Some signaling cascades are extremely complex. One important signaling complex regulates cellular adhesion. Integrins activate Src that phosphorylates a tyrosine kinase Fak. In turn, Fak phosphorylates a variety of cytoskeletal proteins, one of which is paxillin. The formed protein complexes serve as a contact for focal adhesions. Another signaling pathway controls cytoskeletal rearrangement and migration. Src phosphorylates the Rac exchange factor Vav, which activates Rac. In turn, Rac activates a serine kinase PAK (for p21 activated kinase).

Hck-deficient or Fgr-deficient cells have normal neutrophil response to cross-linking of ß2 and ß3 integrins in response to extracellular matrix proteins or monoclonal antibodies, thus illustrating the redundancy of Src family members in the integrin signaling pathway [67 , 68 ]. In double (Hck-/-Fgr-/-) and triple mouse knockouts (Hck-/-Fgr-/-Lyn-/-), neutrophil adhesion and migration is impaired [68 , 100 , 107 ]. Lyn and Fgr in human neutrophils redistribute to cytoskeletal fraction and colocalize with Syk during neutrophil adhesion on fibrinogen-coated surface [108 , 109 ]. The adhesion-dependent activation of neutrophils can be affected by oxidants [110 ]. Diphenylene iodonium, an inhibitor of NADPH oxidase, or degradation of H2O2 by exogenously added catalase inhibits the adhesion-stimulated activities of Fgr and Lyn. When undifferentiated promonocytic HL60 or U937 cells were stimulated with fibronectin or anti-ß1 integrin antibody, Syk becomes activated and tyrosine phosphorylated. In this process, Lyn becomes transiently activated and co-localizes with the actin cytoskeleton [111 , 112 ]. Similarly, cross linking of either CD34 or CD43, sialomucins coexpressed on hematopoietic stem/progenitor cells, activates the signaling pathway for cytoadhesion through Lyn and Syk [113 ]. Stimulation of undifferentiated hematopoietic KG1a cells with anti-CD34 or anti-CD43 induces homotypic cytoadhesion and formation of cap on CD34 and CD43, respectively. The cap colocalized with F-actin. The tyrosine phosphorylation of Lyn, Syk, pp60, pp69, and pp77 was increased at the capping site [113 ]. Similar findings were obtained in monocytic U937 cells ectopically expressing CD34. In addition, normal human CD34+ bone marrow cells showed cap formation of CD34 or CD43 after stimulation. Cbl, an adaptor molecule for Lyn plays an important role in this process: after its phosphorylation, Cbl associated with PI-3 kinase is translocated to the plasma membrane fraction. Although Src kinases are clearly involved in cytoskeletal organization, it is still not completely resolved if they are required for extracellular matrix-mediated assembly of leukocyte adhesion machinery (podosome) and cell motility or whether these kinases transmit signals leading to these events [114 ]. U937 with kinase-defective (K267M) Hck show enhanced adhesiveness and F-actin redistribution. Hck is activated in macrophages after GPIs stimulation [115 ]. Hck is present on the azurophil granules in human granulocytes and translocates toward the phagosomes during phagocytosis. During N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation of human neutrophils or ATRA induction of NB4 cells only Lyn kinase is activated. Zymosan or A23187 stimulation activates both Lyn and Fgr [116 ].

Leukocytes detect chemotactic gradients via GPCR, the best characterized ones being receptors for C5a or fMLP. Although the predominant biochemical effect of GPCR is activation of G proteins and effector enzymes such as phospholipase A2 or adenyl cyclase, cross-talking involving Src PTKs are well documented [117 ]. fMLP-mediated degranulation is markedly diminished in neutrophils treated with the Src inhibitor PP1 or in Src triple-deficient cell lines [118 ]. Perhaps through the ß{gamma} subunits, Src PTKs couple GPCR to MAP kinase. An additional pathway has been found to link GPCR to Src via the {gamma} isoform of PI 3-kinase, which is activated by ß{gamma} subunits [119 ].


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SRC PTKs IN PHAGOCYTOSIS: FC{gamma}R AS A PARADIGM
 
Fc receptors for IgG (Fc{gamma}R), IgE (Fc{varepsilon}R), and IgA (Fc{alpha}R) molecules are expressed on the leukocyte cell surfaces. Signaling through these receptors defines host defense: phagocytosis, cell cytotoxicity, and production and secretion of inflammatory mediators [4 ]. Neutrophils and macrophages are involved in phagocytosis and macrophages and NK cells are involved in antibody-dependent cell-mediated cytotoxicity. After the phagocyte has migrated and accumulated at the site of infection, it engulfs the opsonized bacteria, fungus, or virus. Phagocytosis proceeds through activation of Fc{gamma}R. Three classes of these receptors and their multiple isoforms have highly conserved extracellular domains and distinct intracellular domains. Intracellular domains are of variable length and they have one or two YXXL, conserved tyrosine regions. It is interesting that Fc{gamma}RIIA that lacks a cytoplasmic domain, binds the IgG-coated red blood cells, but it does not mediate erythrocyte phagocytosis. Experiments in COS-1 cells transfected with different isoforms and mutants of Fc{gamma}R showed that both the number and the position of YXXL sequences within cytoplasmic domain are important for phagocytosis. In addition, the differential distribution of Fc{gamma}R isoforms correlate well with their function: isoforms that do not mediate phagocytosis are expressed in lymphoid and myeloid cells that are not phagocytic. Cross-linking of Fc{gamma} receptors leads to activation of tyrosine kinases [120 ] and phosphorylation of ITAMs within receptor cytoplasmic tails [4 ].

Src, Fyn, Fgr, Lck, and Lyn are found in phagocytic cells, where they are associated with the inactive Fc{gamma}Rs [121 122 123 ]. Src-deficient cells were less efficient than the wild-type cells in mediating phagocytosis [124 ]. Phagocytosis is dependent on intact actin microfilaments [125 ]. Cross-linking of Fc{gamma}RI and Fc{gamma}RII on freshly isolated human monocytes leads to transient phosphorylation of PTK Fgr, Syk and FAK, cytoskeletal protein paxillin, and proto-oncogene Vav [126 ]. It is interesting that Hck-deficient and Fgr-deficient macrophages did not have significant reduction in IgG-dependent phagocytosis. In contrast, Hck-/Fgr-/Lyn-deficient macrophages had diminished or delayed phagocytosis, respiratory burst, actin cup formation, and defective activation of Syk and PI3-kinase. However, Hck, Fgr, and Lyn kinases are not absolutely required for Fc{gamma}R-mediated phagocytosis because the phagocytosis did occur, although at low level and delayed [127 ]. Instead, Syk is required for IgG-mediated phagocytosis. Besides phosphorylating ITAMs and contributing to the activation of Syk, recent evidence suggests another function of Src PTK in phagocytosis that leads to changes in actin organization and Ca2+ mobilization [both inositol trisphosphate (IP3)-mediated and IP3-independent]. This is confirmed by studies on Lyn’s role in the context of Fc{varepsilon}RI signaling [128 129 130 ]. Lyn is associated with the ß chain in the inactive receptor and upon activation of receptor, transmits signals for actin organization and Ca2+ mobilization [131 ]. In mast cells Lyn is involved in degranulation mediated by Fc{varepsilon}RI where it associates with soluble tubulin [132 ].


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SRC PTKs IN SURVIVAL: G-CSFR AS A PARADIGM
 
One of the major effects of the hematopoietins (such as G-CSF, erythropoietin, or IL-3) is to maintain the survival by preventing the apoptosis of blood cell progenitors [2 , 133 ]. The factor-dependent 32Dcl3 myeloid cell line has been used to study apoptosis. Retroviral expression of an activated form of Hck markedly prolonged the viability of the factor-dependent murine myeloid cell line, 32Dcl3, in the absence of IL-3 but failed to abrogate the requirement for IL-3 for proliferation [91 ]. Expression of v-Src completely compensated for IL-3-dependent survival and proliferation [134 ]. Additional insights may be gleaned from children with severe congenital neutropenia, who have a defective G-CSF receptor [135 , 136 ]. The likely mechanism of this disorder and cyclic neutropenia is defective anti-apoptosis and maturation [137 , 138 ]. Like that for the TCR, integrins, or Fc receptor (FcR), engagement of the G-CSF receptor leads to subunit dimerization and rapid changes in protein tyrosine phosphorylation of itself and a variety of proximal signaling molecules. The most likely candidates to mediate these phosphorylation events are Janus and Src PTKs [139 ]. Both families of PTKs may be found in association with G-CSF receptor subunits. There are four tyrosine residues in the carboxy-terminal domain of the G-CSF receptor, and several of them become tyrosine phosphorylated. These serve as docking sites for Grb2, STAT, and Lyn or Hck [34 , 140 ]. It is interesting that it is this carboxy-terminal domain that is lacking in some patients with severe congenital neutropenia [136 ]. One major pathway inhibiting apoptosis consists of Src-Cbl-PI3-kinase-PI3-kinase-dependent kinase (PDK)-Akt-Bad (Fig. 6 ) and is activated in a variety of growth factor responses. In Src-dependent fashion, activation of Akt is down-regulated by G-CSF receptor’s carboxy-terminal region [141 ].



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  		Figure 6. Src-Cbl-PI 3-kinase pathway. One important PTK signaling pathway inhibits apoptosis. Src phosphorylates the adaptor molecule Cbl, which activates PI 3-kinase. In turn, a PI 3-kinase-dependent kinase phosphorylates the serine kinase Akt, which phosphorylates Bad. Serine-phosphorylated Bad uncouples from Bcl-2 and promotes resistance to apoptosis.

Src PTKs may also contribute to the promotion of apoptosis. This contradictory behavior is not that surprising because it is also observed in the case of c-Myc [142 ]. Studies in DT40 cells show that Lyn and Syk mediate signaling events involved in radiation-induced apoptosis. Both Lyn and Syk are activated after radiation exposure but with different kinetics: Syk being activated first within 15 s and Lyn within 1 min [143 ]. In addition, DT40 cells deficient in Lyn or Syk undergo apoptosis, suggesting that both kinases may not be required for radiation-induced apoptosis. In contrast, IgM-induced apoptosis was blocked in DT40B cells deficient in Syk or PLC{gamma}2 but was still present in Lyn-deficient cells [144 ]. Adriamycin and etoposide, inhibitors of topoisomerase II, caused apoptosis in DT40 wild-type cells, Syk-deficient, and Btk-deficient cells but Lyn-deficient cells become resistant. Expression of Fyn in Lyn-deficient cells restored apoptosis. Lyn involvement in Topo II inhibitor-induced apoptosis is independent of JNK [145 ]. Lyn-deficient cells are also resistant to ultraviolet-induced apoptosis [146 ]. Like Lyn, Lck also gets activated by radiation. This then leads to caspase-8 activation, which is independent of CD95 ligand expression in T lymphoma cells [147 ]. Ligation of both MHC-I and CD2 on Lck-positive Jurkat cells leads to apoptosis [148 ]. However, ligation of MHC-I on Lck-deficient Jurkat mutant cells (JCaM1.6) did not have any influence on cell signaling or growth. Fyn is also involved in apoptotic pathway in Jurkat cells. Lck mediates TCR-induced apoptosis of mature cycling T cells by controlling Fas ligand expression. Cells treated with Lck antisense oligonucleotides or Lck-defective cell line was not able to induce apoptosis [149 ]. In response to Fas activation, CPP32 or CPP32-like proteinase cleaves Fyn that translocates to the cytoplasm [150 ]. Activated T or B lymphocytes up-regulate the expression of CDw150 receptor, which regulates apoptosis. SHIP and Fgr associate with CDw150 cytoplasmic region. Activation of CDw150 induces dephosphorylation of both SHIP and CDw150 and the association of Lyn and Fgr with SHIP [151 ]. Thus, Src PTKs either promote or inhibit apoptosis depending on the type of stimulus or its context [152 ].


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SRC PTKs AS DRUG TARGETS
 
As we have reviewed, Src PTKs are primarily involved in signal initiation in hematopoietic cells. In addition, some of them have tissue-restricted expression and therefore may be considered as therapeutic targets in autoimmunity, allergic diseases, and cancer. Signal transduction therapeutics based on interrupting tyrosine kinase pathways has been proven through the clinical use of herceptin, a monoclonal antibody that blocks ErbB2 activity in breast cancer. Signal transduction inhibitor 571, a low-molecular-weight compound, inhibits BCRAbl activity in chronic myeloid leukemia. Other pre-clinical studies based on inhibiting Src PTKs by antisense oligonucleotides and low-molecular-weight compounds have shown efficacy in cancer models. For instance, to determine whether Lyn might play a role in supporting acute myeloid leukemia growth, we analyzed fresh or cryopreserved samples from patients. The majority demonstrated constitutive Lyn activity. We have shown that targeting of Lyn by either the antisense technique or Src-specific tyrosine kinase inhibitors will result in profound inhibition of leukemic cell lines, such as HL60, TF-1, and MO7e, or myeloid leukemic blasts [153 ]. Small molecules or antisense oligonucleotides directed against Lyn can also block SCF-induced proliferation, granulocyte-macrophage colony-stimulating factor-dependent neutrophil survival, or IL-5-dependent eosinophil survival [154 155 156 ]. Drugs used to treat cancer, e.g., methotrexate, cyclophosphamide, prednisone, and interferon, have found applications in the management of autoimmune or chronic inflammatory conditions. Based on these observations, inhibitors of Src PTKs and their dependent pathways will be used in the near future for the treatment of non-malignant leukocyte disorders.


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ACKNOWLEDGEMENTS
 
Z. K. M. is supported by the Caligiuri Fellowship and Hirtzel Foundation, and S. J. C. is supported by grants from the National Institutes of Health, American Cancer Society, the Leukemia and Lymphoma Society, the U.S. Department of Agriculture, and the Pittsburgh Foundation.

Received July 22, 2000; revised August 24, 2000; accepted August 29, 2000.


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S. Jeyaseelan, M. S. Kannan, R. E. Briggs, P. Thumbikat, and S. K. Maheswaran
Mannheimia haemolytica Leukotoxin Activates a Nonreceptor Tyrosine Kinase Signaling Cascade in Bovine Leukocytes, Which Induces Biological Effects
Infect. Immun., October 1, 2001; 69(10): 6131 - 6139.
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