Regulation of Ly49D/DAP12 Signal Transduction by Src-Family Kinases and CD45

Mason, Llewellyn H.; Willette-Brown, Jami; Taylor, Lynn S.; McVicar, Daniel W.

doi:10.4049/jimmunol.176.11.6615

Cited by 45 publications

(47 citation statements)

References 65 publications

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“…In contrast cytokine production induced by IL-12 and IL-18 was normal in Bcl10-deficient mice [69]. CD45-deficient mice exhibit decreased cytokine production but normal cytotoxicity [70][71][72]. Receptor tyrosine phosphatase CD45 deficiency augments tyrosine phosphorylation upon stimulation of ITAM-associated receptors, but impairs phosphorylation and activation of Erk, and JNK, abrogating cytokine transcription [71].…”

Section: Regulation Of Cytokine Release By Intracellular Proteinsmentioning

confidence: 99%

Line of attack: NK cell specificity and integration of signals

Bryceson

Long

2008

Current Opinion in Immunology

179

161

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SummaryNatural killer (NK) cells possess potent cytolytic activity and secrete immune modulating cytokines. The large repertoire of NK cell receptors provides versatility for the identification of infected and transformed cells, and for their elimination by NK cells. NK cell responses also stimulate and regulate the adaptive arm of the immune system. We review current knowledge about the molecular specificity of NK cell receptors and about regulation of NK cell effector functions upon encounter with target cells. Mechanisms of recognition, interplay among receptors, signal integration, and dynamic finetuning of NK cell responses are discussed. New insights into molecular checkpoints for NK cell effector function are highlighted and underlying reasons for the complexity in NK cell recognition and signaling are proposed.

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Section: Regulation Of Cytokine Release By Intracellular Proteinsmentioning

confidence: 99%

Line of attack: NK cell specificity and integration of signals

Bryceson

Long

2008

Current Opinion in Immunology

179

161

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“…We observe a modest increase in binding to ICAM-1 using drug doses lower than the IC 50 values for which we presently have no obvious explanation. The Syk and SFKs have been shown to play important roles in the regulation of Ly-49D-dependent responses (14,48,49). SFKs have been shown to play a pivotal role in DAP12 phosphorylation (49) and may promote formation and stability of ADAP/SKAP-55/SLP-76 complexes (45,50,51).…”

Section: Discussionmentioning

confidence: 99%

“…The Syk and SFKs have been shown to play important roles in the regulation of Ly-49D-dependent responses (14,48,49). SFKs have been shown to play a pivotal role in DAP12 phosphorylation (49) and may promote formation and stability of ADAP/SKAP-55/SLP-76 complexes (45,50,51). Similarly, SFKs may modulate LFA-1 binding to ICAM-1 following Ly-49/DAP12 induction by stimulating the activation of Syk kinases directly, and RAP-1 indirectly (49,52,53).…”

Section: Discussionmentioning

confidence: 99%

“…SFKs have been shown to play a pivotal role in DAP12 phosphorylation (49) and may promote formation and stability of ADAP/SKAP-55/SLP-76 complexes (45,50,51). Similarly, SFKs may modulate LFA-1 binding to ICAM-1 following Ly-49/DAP12 induction by stimulating the activation of Syk kinases directly, and RAP-1 indirectly (49,52,53). Interestingly, NKG2D also associates with DAP12 and DAP10 in mouse NK cells (54,55), and it was very recently shown that the NKG2D-dependent elimination of certain tumor cells requires LFA-1 recognition of ICAM-1 (56).…”

Section: Discussionmentioning

confidence: 99%

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Activating Ly-49 Receptors Regulate LFA-1-Mediated Adhesion by NK Cells

Osman

Burshtyn

Kane

2007

The Journal of Immunology

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NK cells are important for innate resistance to tumors and viruses. Engagement of activating Ly-49 receptors expressed by NK cells leads to rapid NK cell activation resulting in target cell lysis and cytokine production. The ITAM-containing DAP12 adapter protein stably associates with activating Ly-49 receptors, and couples receptor recognition with generation of NK responses. Activating Ly-49s are potent stimulators of murine NK cell functions, yet how they mediate such activities is not well understood. We demonstrate that these receptors trigger LFA-1-dependent tight conjugation between NK cells and target cells. Furthermore, we show that activating Ly-49 receptor engagement leads to rapid DAP12-dependent up-regulation of NK cell LFA-1 adhesiveness to ICAM-1 that is also dependent on tyrosine kinases of the Syk and Src families. These results indicate for the first time that activating Ly-49s control adhesive properties of LFA-1, and by DAP12-dependent inside-out signaling. Ly-49-driven mobilization of LFA-1 adhesive function may represent a fundamental proximal event during NK cell interactions with target cells involving activating Ly-49 receptors, leading to target cell death.

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“…19 In some experiments, primary murine NK cells were isolated from splenocytes by positive selection using DX5 beads as per the manufacturer's directions (Miltenyi Biotec, Auburn, CA). Purified NK cells were expanded in vitro using compete media with 1000 U/mL IL-2.…”

Section: Cell Lines and Nk-cell Purificationmentioning

confidence: 99%

Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire

Whittaker

Burshtyn

Orr

et al. 2008

Blood

Self Cite

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(Fc␥RIIIA, CD16). In addition to CD16, NK cells use a variety of receptors that also use immunoreceptor tyrosine-based activation motifs (ITAM) including human NKp30, NKp44, and NKp46 and murine NK1.1 and NKp46. 1 NK cell activation by these receptor complexes is regulated by the coexpression of a vast array of inhibitory receptors that facilitate the determination of "self" versus "nonself." The best characterized of these are the human killer cell immunoglobulinlike receptors (KIR) and the murine Ly49 family of receptors. 2 Originally described as inhibitory receptors, KIRs and Ly49s bind specific major histocompatibility complex (MHC) Class I molecules expressed on healthy cells and prevent lysis by attenuating signal transduction within the NK cell. The result is efficient lysis only of targets deficient in class I expression or that express high enough levels of activating ligands to override the inhibitory signal.Interestingly, not all KIRs or Ly49s are inhibitory. Several members of each family lack characteristic inhibitory motifs and instead carry charged amino acids in their transmembrane domains that mediate interactions with the ITAM-containing signaling chain, DAP12. 3 Engagement of ITAM-containing receptors in NK cells results in tyrosine phosphorylation of the ITAM, followed by recruitment and activation of protein tyrosine kinases of the Syk/ZAP70 family. This results in increased intracellular ionic calcium, activation of Erk-1 and -2 and ultimately IFN␥ production and/or cytotoxicity. [3][4][5] Studies of signal transduction in T cells have identified a variety of complex adaptor proteins, such as the linker for activation of T cells (LAT), that serve to link proximal tyrosine phosphorylation to downstream events. [6][7][8][9] LAT is expressed in T cells, mast cells, and platelets and is rapidly tyrosine-phosphorylated in response to crosslinking of the T-cell antigen receptor (TcR), the high-affinity receptor for IgE on mast cells or GPVI on platelets. 7,10,11 Upon receptor ligation, LAT associates with a variety of Src homology (SH) 2 domain containing proteins including phospholipase C (PLC)-␥1, Vav, SLP76, Grb2 and the 85 kDa regulatory subunit of PI3 kinase. 7 Consistent with its proposed role as a linker between kinases and downstream effector proteins, cotransfection studies have identified LAT as a substrate of both Syk and ZAP-70 and T cells deficient in LAT are deficient in TcR-mediated Ras activation and calcium mobilization. 8,12 LAT is expressed in NK cells and is phosphorylated upon crosslinking of CD16 or during interaction with susceptible, but not resistant, target cells. 13 The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 2869BLOOD, 1 OCTOBER 2008 ⅐ VOLUME 112, NUMBER 7For personal use only. on April 30, 2019. by guest www.bloodjournal.org From an al...

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Regulation of Ly49D/DAP12 Signal Transduction by Src-Family Kinases and CD45

Cited by 45 publications

References 65 publications

Line of attack: NK cell specificity and integration of signals

Line of attack: NK cell specificity and integration of signals

Activating Ly-49 Receptors Regulate LFA-1-Mediated Adhesion by NK Cells

Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire

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