Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis

Shi, Yuhong; Tohyama, Yumi; Kadono, Tomomi; He, Jing; Miah, S. M. Shahjahan; Hazama, Ryoichi; Tanaka, Chika; Tohyama, Kaoru; Yamamura, Hirohei

doi:10.1182/blood-2005-09-3616

Cited by 85 publications

(88 citation statements)

References 39 publications

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“…In both HL-60 and NB4 cells, PMA induces a relevant increase of tyrosine phosphorylation of Vav1 on the Tyr174 residue (Bertagnolo et al, 2011), according to the GEF role played by Vav1 in myeloid cells. These results are also in agreement with other data indicating that, in macrophage-like differentiated HL-60 cells, the activity of Syk is ended to regulate the roles played by mature cells in immune response, including their complement-mediated phagocytosis, in which the kinase regulates both actin dynamics and the Vav1-RhoA activation pathway (Shi et al, 2006). Also in differentiation of APL-derived cells to monocytes/macrophages, a crucial role for Vav1 in determining the acquisition of maturation-related features has been demonstrated by silencing the expression of Vav1 induced by PMA (Bertagnolo et al, 2011).…”

Section: Vav1 and Monocytic/macrophagic Differentiationsupporting

confidence: 82%

“…Experiments performed with HL-60 cells have demonstrated the association of tyrosine phosphorylated Syk with the Vav1-SH2 domain, in both whole cell and nuclear compartment, as a consequence of ATRA treatment (Bertagnolo et al, 2001). These data are in agreement with the notion that activation of Syk occurs in differentiating HL-60 cells (Qin & Yamamura, 1997) and mature neutrophils, in which it regulates migration (Schymeinsky et al, 2006) and the formation of lamellipodia during phagocytosis (Shi et al, 2006). While in whole HL-60 cells the Vav1/Syk association takes place regardless of their phosphorylation level and of ATRA treatment, the formation of Vav1/Syk complexes inside the nuclear compartment strongly increases during the differentiation process, suggesting a specific role for this tyrosine kinase in the nucleus.…”

Section: Tyrosine Phosphorylation Of Vav1supporting

confidence: 81%

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Vav1: A Key Player in Agonist-Induced Differentiation of Promyelocytes from Acute Myeloid Leukemia (APL)

Bertagnolo¹,

Brugnoli²,

Capitani³

2011

Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

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Section: Vav1 and Monocytic/macrophagic Differentiationsupporting

confidence: 82%

Section: Tyrosine Phosphorylation Of Vav1supporting

confidence: 81%

Vav1: A Key Player in Agonist-Induced Differentiation of Promyelocytes from Acute Myeloid Leukemia (APL)

Bertagnolo¹,

Brugnoli²,

Capitani³

2011

Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

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“…Syk is a tyrosine kinase that has been shown to be critical for various immune cell functions, including cytoskeletal rearrangements and phagocytosis 19,20 . Thus, in this study we specifically examined the role of Syk in the uptake of Francisella.…”

Section: Introductionmentioning

confidence: 99%

The tyrosine kinase Syk promotes phagocytosis of Francisella through the activation of Erk

Parsa

Butchar

Rajaram

et al. 2008

Molecular Immunology

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Francisella tularensis is a highly infectious, Gram-negative intra-cellular pathogen that can cause the zoonotic disease tularemia. Although the receptors critical for internalization of Francisella by macrophages are beginning to be defined, the identity of the downstream signaling pathways essential for the engulfment are not yet identified. In this study we have tested the role of Syk in the phagocytosis of Francisella. We report that Syk is activated during Francisella infection and is critical for the uptake of the organisms. Pharmacologic inhibition of Syk almost completely abrogated uptake, whereas the overexpression of Syk significantly enhanced uptake. However, Syk appears to be dispensable during initial host-pathogen contact. Further analyses of the molecular mechanism of Syk influence on Francisella uptake revealed that the MAPK Erk but not the PI3K/Akt pathway is the downstream effector of Syk. Thus, the inhibition of Erk in Syk-overexpressing cells or the inhibition of Syk in Erk-overexpressing cells led to a significant attenuation of uptake. Collectively, these data identify Syk and Erk as key players in the phagocytosis of Francisella.

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“…The phosphorylation of ITAMs allows binding and activation of the nonreceptor tyrosine kinase Syk (16,17). Previous studies have demonstrated a crucial role of Syk for different b 2 integrin-mediated PMN functions, including slow leukocyte rolling and firm adhesion during inflammation in vivo, as well as the respiratory burst, cell spreading, migration, and phagocytosis (4,16,(18)(19)(20)(21)(22)(23)(24). Signaling downstream of Syk involves several molecules, including phospholipase C-g, the guanine nucleotide exchange factor Vav, the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa, the adaptor protein Cbl, and the regulatory subunit p85 of the PI3K class I A (18,22,(25)(26)(27)(28)(29)(30).…”

mentioning

confidence: 99%

The Mammalian Actin-Binding Protein 1 Is Critical for Spreading and Intraluminal Crawling of Neutrophils under Flow Conditions

Hepper

Schymeinsky

Weckbach

et al. 2012

The Journal of Immunology

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Recently, the mammalian actin-binding protein 1 (mAbp1; Hip-55, SH3P7, debrin-like protein) was identified as a novel component of the β2 integrin-mediated signaling cascade during complement-mediated phagocytosis and firm adhesion of polymorphonuclear neutrophils (PMN) under physiological shear stress conditions. In this study, we found that the genetic ablation of mAbp1 severely compromised not only the induction of adhesion, but also subsequent spreading of leukocytes to the endothelium as assessed by intravital microscopy of inflamed vessels of the cremaster muscle of mice. In vitro studies using murine PMN confirmed that mAbp1 was required for β2 integrin-mediated spreading under shear stress conditions, whereas mAbp1 was dispensable for spreading under static conditions. Upon β2 integrin-mediated adhesion and chemotactic migration of human neutrophil-like differentiated HL-60 cells, mAbp1 was enriched at the leading edge of the polarized cell. Total internal reflection fluorescence microscopy revealed that mAbp1 formed propagating waves toward the front of the lamellipodium, which are characteristic for dynamic reorganization of the cytoskeleton. Accordingly, binding of mAbp1 to actin was increased upon β2 integrin-mediated adhesion, as shown by coimmunoprecipitation experiments. However, chemotactic migration under static conditions was unaffected in the absence of mAbp1. In contrast, the downregulation of mAbp1 by RNA interference technique in neutrophil-like differentiated HL-60 cells or the genetic ablation of mAbp1 in leukocytes led to defective migration under flow conditions in vitro and in inflamed cremaster muscle venules in the situation in vivo. In conclusion, mAbp1 is of fundamental importance for spreading and migration under shear stress conditions, which are critical prerequisites for efficient PMN extravasation during inflammation.

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Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis

Cited by 85 publications

References 39 publications

Vav1: A Key Player in Agonist-Induced Differentiation of Promyelocytes from Acute Myeloid Leukemia (APL)

Vav1: A Key Player in Agonist-Induced Differentiation of Promyelocytes from Acute Myeloid Leukemia (APL)

The tyrosine kinase Syk promotes phagocytosis of Francisella through the activation of Erk

The Mammalian Actin-Binding Protein 1 Is Critical for Spreading and Intraluminal Crawling of Neutrophils under Flow Conditions

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