Kit- and FcɛRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells

Iwaki, Shoko; Špička, Jiřı́; Tkaczyk, Christine; Jensen, Bettina M.; Furumoto, Yasuko; Charles, Nicolas; Kovářová, Martina; Rivera, Juan; Hořejšı́, Václav; Metcalfe, Dean D.; Gilfillan, Alasdair M.

doi:10.1016/j.cellsig.2007.10.013

Cited by 58 publications

(69 citation statements)

References 42 publications

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“…PAG-WT cells released increasing amounts of ␤-glucuronidase when activated with 25 to 200 ng/ml SCF. The extent of SCF-induced degranulation was higher than that described in previous studies (50,51) and was apparently related to the growth of bone marrow cells in the presence of both IL-3 and SCF. When BMMCs were derived from cultures containing IL-3 alone, their SCF-induced degranulation was low (45).…”

Section: Resultscontrasting

confidence: 43%

Transmembrane Adaptor Protein PAG/CBP Is Involved in both Positive and Negative Regulation of Mast Cell Signaling

Dráberová

Potůčková

Hálová

et al. 2014

Molecular and Cellular Biology

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The transmembrane adaptor protein PAG/CBP (here, PAG) is expressed in multiple cell types. Tyrosine-phosphorylated PAG serves as an anchor for C-terminal SRC kinase, an inhibitor of SRC-family kinases. The role of PAG as a negative regulator of immunoreceptor signaling has been examined in several model systems, but no functions in vivo have been determined. Here, we examined the activation of bone marrow-derived mast cells (BMMCs) with PAG knockout and PAG knockdown and the corresponding controls. Our data show that PAG-deficient BMMCs exhibit impaired antigen-induced degranulation, extracellular calcium uptake, tyrosine phosphorylation of several key signaling proteins (including the high-affinity IgE receptor subunits, spleen tyrosine kinase, and phospholipase C), production of several cytokines and chemokines, and chemotaxis. The enzymatic activities of the LYN and FYN kinases were increased in nonactivated cells, suggesting the involvement of a LYN-and/or a FYNdependent negative regulatory loop. When BMMCs from PAG-knockout mice were activated via the KIT receptor, enhanced degranulation and tyrosine phosphorylation of the receptor were observed. In vivo experiments showed that PAG is a positive regulator of passive systemic anaphylaxis. The combined data indicate that PAG can function as both a positive and a negative regulator of mast cell signaling, depending upon the signaling pathway involved. Mast cells are widely distributed in the body, where they play important roles in innate as well as adaptive immune responses (1). To fulfill their role in adaptive immune responses, the cells express the high-affinity IgE receptor FcεRI on their plasma membranes. Aggregation of this tetrameric immunoreceptor, ␣␤␥2, induces cell signaling events leading to the release of preformed inflammatory mediators and the de novo synthesis and release of leukotrienes, cytokines, and chemokines. The first welldefined biochemical step after FcεRI triggering is tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motifs in the cytoplasmic tail of the FcεRI ␤ and ␥ subunits by the SRC family protein tyrosine kinase (PTK) LYN (2, 3). The phosphorylated ␤ and ␥ subunits then serve as binding and activation sites for LYN kinase and spleen tyrosine kinase (SYK), respectively. These two enzymes, together with FYN and other kinases, then phosphorylate various adaptor proteins and enzymes with a variety of functions in signal transduction pathways. The exact molecular events preceding LYN-mediated tyrosine phosphorylation of the FcεRI ␤ subunit are not clear, and several models have been proposed, including the transphosphorylation model (4), the lipid raft model (5), and the PTK-protein tyrosine phosphatase (PTP) interplay model (6).Our previous study with murine bone marrow-derived mast cells (BMMCs) showed that FcεRI triggering induced transient hyperphosphorylation of LYN kinase on its C-terminal regulatory tyrosine (Tyr 487), leading to the formation of a closed inactive conformation where the SRC homology 2 (...

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Section: Resultscontrasting

confidence: 43%

Transmembrane Adaptor Protein PAG/CBP Is Involved in both Positive and Negative Regulation of Mast Cell Signaling

Dráberová

Potůčková

Hálová

et al. 2014

Molecular and Cellular Biology

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“…Thus, c-Kit can phosphorylate NTAL directly, whereas FceRI only indirectly through Lyn or Syk kinase. Importantly, Syk and c-Kit phosphorylate different tyrosines in NTAL, which then serve as direct or indirect binding sites for different kinases, phosphatases and other enzymes [10]. Different ways of cell activation could lead to formation of different NTAL signalosomes and therefore different performance of the cells in such complex processes as migration, spreading and degranulation.…”

Section: Discussionmentioning

confidence: 99%

“…After c-kit receptor engagement, NTAL becomes phosphorylated. In human and murine mast cells, FceRI-and SCF-mediated NTAL phosphorylations are regulated differentially by Src family kinases and c-kit, respectively [10].…”

Section: Introductionmentioning

confidence: 99%

The transmembrane adaptor protein NTAL signals to mast cell cytoskeleton via the small GTPase Rho

et al. 2010

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The transmembrane adaptor protein NTAL (non-T-cell activation linker) participates in signalosome assembly in hematopoietic cells, but its exact role in cell physiology remains enigmatic. We report here that BM-derived mast cells from NTAL-deficient mice, responding to Ag alone or in combination with SCF, exhibit reduced spreading on fibronectin, enhanced filamentous actin depolymerization and enhanced migration towards Ag relative to WT cells. No such differences between WT and NTAL À/À BM-derived mast cells were observed when SCF alone was used as activator. We have examined the activities of two small GTPases, Rac and Rho, which are important regulators of actin polymerization. Stimulation with Ag and/or SCF enhanced activity of Rac(1,2,3) in both NTAL À/À and WT cells. In contrast, RhoA activity decreased and this trend was much faster and more extensive in NTAL À/À cells, indicating a positive regulatory role of NTAL in the recovery of RhoA activity. After restoring NTAL into NTAL À/À cells, both spreading and actin responses were rescued. This is the first report of a crucial role of NTAL in signaling, via RhoA, to mast cell cytoskeleton.

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“…SH2 domain containing leukocyte protein of 76 kDa is needed for FcgR-mediated ROS production in neutrophils (13), but not in macrophages (14,15), which may be because of differential FcgR expression. Linker for activation of T cells (LAT) and LAT2 can be phosphorylated by Syk and Src kinase Lyn (16,17) and have been shown to be critically involved in myeloid ITAM signaling (18)(19)(20). It has been suggested that FcgRI, but not FcgRIIa, cross-linking leads to phosphorylation of LAT2 in the human monocytic cell line THP-1.…”

Section: Fcgri Downstream Signalingmentioning

confidence: 99%

Functional Characteristics of the High Affinity IgG Receptor, FcγRI

Poel¹,

Spaapen

Winkel

et al. 2011

The Journal of Immunology

154

114

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IgG FcRs are important mediators of immunity and play a key role during Ab-based immunotherapy. Within the leukocyte IgG receptor family, only FcγRI is capable of IgG binding with high affinity. FcγRI exists as a complex of a ligand binding α-chain and an FcR γ-chain. The receptors’ α-chain can, furthermore, elicit several functions independent of the ITAM-bearing FcR γ-chain. Functional implications of high-affinity IgG binding and mechanisms underlying FcR γ-chain–independent signaling remain unclear to this day. In this paper, we provide an overview of past literature on FcγRI and address the implications of recently described interactions between cytosolic proteins and the FcγRI α-chain, as well as cytokine-enhanced FcγRI immune complex binding. Furthermore, an analysis of potential polymorphisms within the FCGR1A gene is provided.

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Kit- and FcɛRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells

Cited by 58 publications

References 42 publications

Transmembrane Adaptor Protein PAG/CBP Is Involved in both Positive and Negative Regulation of Mast Cell Signaling

Transmembrane Adaptor Protein PAG/CBP Is Involved in both Positive and Negative Regulation of Mast Cell Signaling

The transmembrane adaptor protein NTAL signals to mast cell cytoskeleton via the small GTPase Rho

Functional Characteristics of the High Affinity IgG Receptor, FcγRI

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