Syk Regulation of Phosphoinositide 3-Kinase-Dependent NK Cell Function

Jiang, Kun; Zhong, Bin; Gilvary, Danielle L.; Corliss, Brian C.; Vivier, Éric; Hong-Geller, Elizabeth; Wei, Sheng; Djeu, Julie Y.

doi:10.4049/jimmunol.168.7.3155

Cited by 110 publications

(85 citation statements)

References 57 publications

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“…Consequently, inhibition of NF-κB activation by piceatannol might be dependent on down-regulation of Akt-mediated IKK-α and Raf-1 phosphorylation. Akt is regulated by phosphatidylinositol 3 (PI3)-kinase, and the Akt/PI3 kinase signal pathway is activated by Syk in B cells (4,18,31). Therefore, it is possible that piceatannol, a potent inhibitor of Syk, inhibits LPS-induced NO production and NF-κB activation via the Akt/PI3 kinase signal pathway.…”

Section: Discussionmentioning

confidence: 99%

Piceatannol Prevents Lipopolysaccharide (LPS)‐Induced Nitric Oxide (NO) Production and Nuclear Factor (NF)‐κB Activation by Inhibiting IκB Kinase (IKK)

Islam

Hassan

et al. 2004

Microbiology and Immunology

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., 48(10), [729][730][731][732][733][734][735][736] 2004 Abbreviations: ELISA, enzyme-linked immuno sorbent assay; Erk, extracellular signal regulated kinase; IKK, IκB kinase; iNOS, inducible isoform of NO synthase; LPS, lipopolysaccharide; MAP kinase, mitogen-activated protein kinase; MTT, 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide; NF-κB, nuclear factor-κB; NO, nitric oxide; SAPK/JNK, stressactivated protein kinase/c-Jun NH2-terminal kinase; SDS, sodium dodecylsulfate; TNF, tumor necrosis factor.

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Section: Discussionmentioning

confidence: 99%

Piceatannol Prevents Lipopolysaccharide (LPS)‐Induced Nitric Oxide (NO) Production and Nuclear Factor (NF)‐κB Activation by Inhibiting IκB Kinase (IKK)

Islam

Hassan

et al. 2004

Microbiology and Immunology

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“…In some assays, NK tumor cell lines NK92 and NKL or PBMCs were cultured with 100 IU/mL IL-2-containing medium were used as effector cells. 25 …”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors

Epling-Burnette

Bai

Painter

et al. 2007

Blood

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200

171

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Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis with potential for progression to acute myeloid leukemia (AML). We compared natural killer (NK) cytolytic function in 48 MDS patients with 37 healthy donors and found reduced activity in the patient population (K562 cytolysis, 19% ؎ 21% SD versus 40% ؎ 17%) (P < .001). NK cytotoxicity in MDS patients was reduced against 3 disparate tumor targets with differential activating receptor requirement, suggesting global defects in NK function. Reduced NK function in MDS was significantly associated with higher International Prognostic Score (P ‫؍‬ .01), abnormal karyotype (P ‫؍‬ .05), the presence of excess blasts (P ‫؍‬ .01), and ageadjusted bone marrow hypercellularity (P ‫؍‬ .04). MDS patients had a display of the activating receptor NKp30, and NKG2D down-regulation closely correlated with impaired NK function (P ‫؍‬ . IntroductionThe myelodysplastic syndromes (MDS) are stem cell malignancies that display hematologic heterogeneity but share features of ineffective hematopoiesis and a potential for progression to acute myeloid leukemia (AML). 1,2 Multiple factors have been implicated in the pathogenesis of MDS, including cytogenetic and molecular abnormalities and disturbance in cellular immunity. Abnormal natural killer (NK) function, including reduced antibody-dependent cell cytotoxicity (ADCC) and diminished direct NK cell cytolytic function, have been previously described; however, the biologic mechanisms underlying these changes have not be defined. [3][4][5][6][7] Normal NK cells, ␥␦ T cells, and some ␣␤ T cells mediate their biologic action through 3 families of NK receptors: killer cell immunoglobulin-like receptors (KIRs), C lectin-like (NKG2) family receptors, and natural cytotoxicity receptors ([NCRs] eg, NKp30, NKp44, and NKp46). 8 Regulation of innate immunity occurs through balanced signaling by these families of NK receptors with activating and inhibitory function. [9][10][11] Constitutively expressed activating receptors such as NKp46 and NKp30 along with NKG2D mediate most non-major histocompatibility complex (non-MHC)-induced tumor-specific cytotoxicity by NK cells, and the activation-restricted NCR (NKp44) increases NK cytotoxicity after cytokine activation. 12 Although many NK receptors with both activating and inhibitory function have been identified and details of their downstream signaling pathways have been elucidated, a void exists in the identification of activatory NK ligands and the pathologic situations in which they are induced in tumor and virally infected cells. The best-characterized NK receptor ligands are the stress-inducible MHC class I-related chain A (MICA), MICB, and UL16-binding proteins (ULBPs), which constitute the major cellular ligands for human NKG2D. [13][14][15][16][17] In addition to viralinduced expression, NKG2D ligands are often expressed by tumor cells. 18,19 Ligands for NKp30, NKp44, and NKp46 have not yet been delineated.In MDS, the pathogenesis and clinical implications of reduced NK ...

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“…Syk also is required for the activation of phosphoinositide 3-kinase (PI3K) in response to a variety of signals (12)(13)(14)(15)(16)(17)(18) including engagement of the B cell antigen receptor (BCR) (12) and macrophage or neutrophil Fc␥ receptors (13,14). Furthermore, the expression of a constitutively active TEL-Syk fusion protein in atypical myelodysplastic syndrome leads to the constitutive activation of PI3K (19).…”

mentioning

confidence: 99%

Molecular Basis for a Direct Interaction between the Syk Protein-tyrosine Kinase and Phosphoinositide 3-Kinase

Moon

Post

Durden

et al. 2005

Journal of Biological Chemistry

101

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After engagement of the B cell receptor for antigen, the Syk protein-tyrosine kinase becomes phosphorylated on multiple tyrosines, some of which serve as docking sites for downstream effectors with SH2 or other phosphotyrosine binding domains. The most frequently identified binding partner for catalytically active Syk identified in a yeast two-hybrid screen was the p85 regulatory subunit of phosphoinositide 3-kinase. The C-terminal SH2 domain of p85 was sufficient for mediating an interaction with tyrosine-phosphorylated Syk. Interestingly, this domain interacted with Syk at phosphotyrosine 317, a site phosphorylated in trans by the Src family kinase, Lyn, and identified previously as a binding site for c-Cbl. This site interacted preferentially with the p85 C-terminal SH2 domain compared with the c-Cbl tyrosine kinase binding domain. Molecular modeling studies showed a good fit between the p85 SH2 domain and a peptide containing phosphotyrosine 317. Tyr-317 was found to be essential for Syk to support phagocytosis mediated by Fc␥RIIA receptors expressed in a heterologous system. These studies establish a new type of p85 binding site that can exist on proteins that serve as substrates for Src family kinases and provide a molecular explanation for observations on direct interactions between Syk and phosphoinositide 3-kinase.Syk is a 72-kDa protein-tyrosine kinase that plays a central role in coupling immune recognition receptors to multiple downstream signaling pathways (1,2). This function is a property of both its catalytic activity and its ability to participate in interactions with effector proteins containing SH2 1 domains.For example, after the engagement of antigen receptors on B cells, Syk is phosphorylated on three tyrosines that lie within the linker B region, which separates the N-terminal tandem pair of SH2 domains from the catalytic domain (3). Phosphorylation of the first, at Tyr-317 (numbering based on the murine Syk sequence), is catalyzed primarily by Lyn, a Src family kinase. This creates a docking site for c-Cbl, a potential negative regulator of Syk-dependent signaling (4, 5). Indeed, mutant forms of Syk containing substitutions of Phe for Tyr at position 317 exhibit enhanced activity in B cells and mast cells (3,5,6). To date, c-Cbl is the only protein identified that is capable of binding to Syk at pTyr-317. Phosphorylation of Tyr-342 and 346 forms a docking site for multiple SH2 domaincontaining proteins including phospholipase C-␥, Vav, and Fgr (7-10). Mutant forms of Syk containing substitutions of Phe for Tyr-342 or both Tyr-342 and 346 exhibit a reduced ability to couple immune recognition receptors to the activation of downstream effectors such as phospholipase C-␥2 in B cells and mast cells (10, 11).Syk also is required for the activation of phosphoinositide 3-kinase (PI3K) in response to a variety of signals (12-18) including engagement of the B cell antigen receptor (BCR) (12) and macrophage or neutrophil Fc␥ receptors (13,14). Furthermore, the expression of a constitutively active ...

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Syk Regulation of Phosphoinositide 3-Kinase-Dependent NK Cell Function

Cited by 110 publications

References 57 publications

Piceatannol Prevents Lipopolysaccharide (LPS)‐Induced Nitric Oxide (NO) Production and Nuclear Factor (NF)‐κB Activation by Inhibiting IκB Kinase (IKK)

Piceatannol Prevents Lipopolysaccharide (LPS)‐Induced Nitric Oxide (NO) Production and Nuclear Factor (NF)‐κB Activation by Inhibiting IκB Kinase (IKK)

Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors

Molecular Basis for a Direct Interaction between the Syk Protein-tyrosine Kinase and Phosphoinositide 3-Kinase

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