Aggregation of the high-affinity IgE receptor and enhanced activity of p53/56lyn protein-tyrosine kinase.

Yamashita, Toshiyuki; Mao, Su-Yau; Metzger, Henry

doi:10.1073/pnas.91.23.11251

Cited by 164 publications

(146 citation statements)

References 17 publications

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“…Although previous results have explained how the phosphorylation of Fc⑀RI ␤ and ␥ and subsequent events proceed after the association of active Lyn with a receptor cluster (23, 25, 38, 39), the structural basis for the initial interaction between Lyn and Fc⑀RI in the activation process has remained poorly defined. Several studies that detected association of Lyn with unstimulated Fc⑀RI utilized methods that could stabilize the association of these receptors with membrane domains, including chemical cross-linking (18) or low detergent:cell lipid ratios (23). We find that unstimulated receptors do not co-isolate with the Lyn-containing domains to a large extent (Fig.…”

Section: Resultsmentioning

confidence: 62%

Compartmentalized Activation of the High Affinity Immunoglobulin E Receptor within Membrane Domains

Field

Holowka

Baird

1997

Journal of Biological Chemistry

320

344

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The earliest known step in the activation of the high affinity IgE receptor, Fc⑀RI, is the tyrosine phosphorylation of its ␤ and ␥ subunits by the Src family tyrosine kinase, Lyn. We report here that aggregation-dependent association of Fc⑀RI with specialized regions of the plasma membrane precedes its tyrosine phosphorylation and appears necessary for this event. Tyrosine phosphorylation of ␤ and ␥ occurs in intact cells only for Fc⑀RI that associate with these detergent-resistant membrane domains, which are enriched in active Lyn. Furthermore, efficient in vitro tyrosine phosphorylation of Fc⑀RI subunits occurs only for those associated with isolated domains. This association and in vitro phosphorylation are highly sensitive to low concentrations of detergent, suggesting that lipid-mediated interactions with Lyn are important in Fc⑀RI activation. Participation of membrane domains accounts for previously unexplained aspects of Fc⑀RI-mediated signaling and may be relevant to signaling by other multichain immune receptors.The plasma membrane contains specialized regions that have distinct compositions and can serve unique functions in the regulation of cell surface receptor activation. For example, caveolae have been shown to associate with certain signaling proteins (1, 2) and have been implicated in receptor activation (3-6), vesicular transport (7,8), and the uptake of small molecules (9). Compositionally related membrane domains, which lack the invaginated morphology of caveolae as well as the membrane protein caveolin, have also been identified and biochemically separated from caveolae (10). These membrane domains, like caveolae, are resistant to solubilization in nonionic detergents such as Triton X-100, are enriched in sphingolipids and glycosylphosphatidylinositol-linked proteins, and are associated with palmitoyl-anchored signaling molecules including Src family tyrosine kinases (10 -14). Detergent-resistant membrane domains isolated from rat basophilic leukemia (RBL) 1 cells, a mast cell line, contain at least 30% of the cellular Lyn, a Src family tyrosine kinase, and no detectable caveolin (15).Aggregation of Fc⑀RI on mast cells and basophils by multivalent antigens leads to phosphorylation of immunoreceptor tyrosine-based activation motifs within the ␤ and ␥ receptor subunits by . This initiates a signaling cascade culminating in secretion of inflammatory mediators and cytokines that play an important role in the allergic response (20, 21). The molecular mechanism by which aggregation of Fc⑀RI initiates its phosphorylation by Lyn is incompletely understood. Selective binding of Lyn directly to unphosphorylated Fc⑀RI ␤ (22) has been proposed to mediate an initial transphosphorylation of aggregated Fc⑀RI (23), but this does not account for the capacity of Fc⑀RI lacking the ␤ subunit (24, 25) or chimeric receptors containing only the ␥ cytoplasmic tail (26 -28) to become tyrosine-phosphorylated upon aggregation. The involvement of detergent-resistant membrane domains in Fc⑀RI signaling was recently sugge...

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Section: Resultsmentioning

confidence: 62%

Compartmentalized Activation of the High Affinity Immunoglobulin E Receptor within Membrane Domains

Field

Holowka

Baird

1997

Journal of Biological Chemistry

320

344

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“…Yeast two-hybrid studies (8) indicated that the unique domain of both Lyn A and Lyn B could bind directly to the unphosphorylated C-terminal cytoplasmic domain of the Fc⑀RI ␤-chain, while peptide-binding studies (9,13) indicated that the SH2 domain of Lyn bound to phosphorylated Fc⑀RI ␤ ITAMs. Furthermore, chemical cross-linking studies demonstrated that 5% of total cellular Lyn in rat basophilic leukemia (RBL)-2H3 cells was bound to resting, unphosphorylated receptors (7). The Lyn unique domain appears to be the sole site of interaction with resting IgE receptors because an equivalent strength of association, as measured by production of ␤-galactosidase, was present between the unique domain and full-length Lyn protein in yeast two-hybrid studies (8).…”

Section: Regulation Of Rat Basophilic Leukemia-2h3 Mast Cellmentioning

confidence: 99%

“…The MIRR family receptors initiate signaling by tyrosine phosphorylation of their ITAMs by noncovalently associated Src family tyrosine kinases (3)(4)(5)(6). A common feature of the kinase-receptor interaction is a constitutive association between a small fraction of the total kinase with resting, i.e., unphosphorylated receptors, mediated by the unique domain of each kinase (7,8). After aggregation of the MIRR family receptors, the Src family kinases reorient and bind to the phosphorylated receptor ITAMs via their Src homology 2 (SH2) domains (9).…”

Section: Regulation Of Rat Basophilic Leukemia-2h3 Mast Cellmentioning

confidence: 99%

Regulation of Rat Basophilic Leukemia-2H3 Mast Cell Secretion by a Constitutive Lyn Kinase Interaction with the High Affinity IgE Receptor (FcεRI)

Vonakis

Gibbons

Rotté

et al. 2005

The Journal of Immunology

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Signaling through the high affinity IgE receptor is initiated by noncovalently associated Lyn kinase, resulting in the secretion of inflammatory mediators from mast cells. A fraction of the total cellular Lyn is associated via its N-terminal unique domain with the cytoplasmic domain of the FcεRI β subunit before receptor aggregation. In the current study, we stably transfected the unique domain of Lyn into rat basophilic leukemia-2H3 mast cells and examined the consequences on FcεRI-induced signal transduction and mediator secretion to further define the role of the unique domain of Lyn in mast cell secretion. Tyrosine phosphorylation of FcεRI β and γ subunits was partially inhibited in the Lyn unique domain transfectants after Ag stimulation. Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK-2, which are required for leukotriene C4 (LTC4) release, and production of LTC4 was increased 3- to 5-fold, compared with cells transfected with vector alone. Conversely, tyrosine phosphorylation of the adaptor protein Gab2, which is essential for mast cell degranulation, was inhibited after Ag stimulation of Lyn unique domain transfectants, and Ag-induced release of histamine was inhibited up to 48%. In rat basophilic leukemia-2H3 cells, Lyn thus plays a dual role by positively regulating FcεRI phosphorylation and degranulation while negatively regulating LTC4 production. This study provides further evidence that the constitutive interaction between the unique domain of Lyn and the FcεRI β subunit is a crucial step in the initiation of FcεRI signaling and that Lyn is limiting for FcεRI-induced secretion of inflammatory mediators.

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“…Fc 4 RI cross-linking by multivalent Ag-IgE complexes facilitates the transphosphorylation of one receptor by Lyn bound to a juxtaposed receptor. Tyrosine phosphorylation of Fc 4 RI subunits facilitates the recruitment of additional Lyn and Syk to the Fc 4 RI g and + subunit, respectively, and further propagation of the activation signal [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Differential sensitivity to acute cholesterol lowering of activation mediated via the high-affinity IgE receptor and Thy-1 glycoprotein

et al. 2001

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Aggregation of the high-affinity IgE receptor and enhanced activity of p53/56lyn protein-tyrosine kinase.

Cited by 164 publications

References 17 publications

Compartmentalized Activation of the High Affinity Immunoglobulin E Receptor within Membrane Domains

Compartmentalized Activation of the High Affinity Immunoglobulin E Receptor within Membrane Domains

Regulation of Rat Basophilic Leukemia-2H3 Mast Cell Secretion by a Constitutive Lyn Kinase Interaction with the High Affinity IgE Receptor (FcεRI)

Differential sensitivity to acute cholesterol lowering of activation mediated via the high-affinity IgE receptor and Thy-1 glycoprotein

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