Function of human FcγRIIA and FcγRIIIB

Unkeless, Jay C.; Zhang, Shen; Lin, Chou-Wen; DeBeus, Elizabeth

doi:10.1016/1044-5323(95)90006-3

Cited by 101 publications

(38 citation statements)

References 61 publications

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“…In neutrophils, a range of GPI-anchored proteins interact with and signal via tyrosine kinases (14,30,45). The Src family of nonreceptor tyrosine kinases, most notably (although not exclusively) c-Src, is frequently overexpressed or aberrantly activated in epithelial and nonepithelial cancers and has functions that are critical in primary tumor progression and metastasis (27,46,47).…”

Section: Discussionmentioning

confidence: 99%

CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells

Duxbury

Ito

Ashley

et al. 2004

Journal of Biological Chemistry

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Despite lacking transmembrane or intracellular domains, glycosylphosphatidylinositol-anchored proteins can modulate intracellular signaling events, in many cases through aggregation within membrane "lipid raft" microdomains. CEACAM6 is a glycosylphosphatidylinositol-linked cell surface protein of importance in the anchorage-independent survival and metastasis of pancreatic adenocarcinoma cells. We examined the effects of antibody-mediated cross-linking of CEACAM6 on intracellular signaling events and anchorage-independent survival of the CEACAM6-overexpressing pancreatic ductal adenocarcinoma cell line, BxPC3. CEACAM6 cross-linking increased c-Src activation and induced tyrosine phosphorylation of p125 FAK focal adhesion kinase. Focal adhesion kinase phosphorylation was dependent on c-Src kinase activation, for which caveolin-1 was required. CEACAM6 cross-linking induced a significant increase in cellular resistance to anoikis. These observations represent the first characterization of the mechanism through which this important cell surface oncoprotein influences intracellular signaling events and hence malignant cellular behavior. CEACAM61 is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein that is overexpressed in a variety of human malignancies, including pancreatic adenocarcinoma (1, 2). This immunoglobulin superfamily member is emerging as an important determinant of a variety of aspects of the malignant cellular phenotype (1-3). We reported previously that levels of CEACAM6 expression modulate the susceptibility of pancreatic adenocarcinoma cells to anoikis (2). Normal epithelial cells require anchorage to an extracellular matrix for growth, survival, and differentiation. Resistance to anoikis, a subset of apoptosis induced by inadequate or inappropriate cell-substrate contact in normal cells, is a property of transformed cells that is associated with enhanced tumorigenesis and metastatic ability. Despite clear indications of its important role in cancer cell biology, the mechanisms through which CEACAM6 influences intracellular signal transduction remain poorly understood.Despite lacking transmembrane and intracellular domains, several GPI-anchored proteins, including CEACAM family members, are able to influence intracellular events and have been implicated in transmembrane signaling via tyrosine kinases (4 -7). GPI-anchored proteins are known to exist in clusters and form microdomains at the surface of the plasma membrane, referred to as "lipid rafts" (8). These microdomains appear to be important for GPI-anchored protein signal transduction. A number of signal transduction components, including Src family tyrosine kinases, are associated with lipid rafts, and cross-linking of cell surface molecules by a variety of techniques has proven to be a useful tool for exploring the functional roles of raft-associated proteins (9 -14).Here, we examine the effects of antibody-mediated crosslinking of CEACAM6 in pancreatic adenocarcinoma cells. We determine the effects of CEACAM6 cross-linking on ...

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Section: Discussionmentioning

confidence: 99%

CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells

Duxbury

Ito

Ashley

et al. 2004

Journal of Biological Chemistry

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“…8A, SFT in top plot). As expected, GPI anchored CD14 and the neutrophil membrane protein Fc␥RIIIB (CD16), both known raft markers (43,44), were stable to detergent extraction both before and after fixation (Figs. 7A, and 8A, top plot).…”

Section: Cxcr1 and Cxcr2 Endocytosis And Early Signaling Eventsmentioning

confidence: 83%

“…7A, and 8A, top plot). Another Fc receptor, Fc␥RIIA (CD32), which is not GPI anchored (44), also resisted detergent extraction (Fig. 8A, top plot).…”

Section: Cxcr1 and Cxcr2 Endocytosis And Early Signaling Eventsmentioning

confidence: 99%

On the Mechanism and Significance of Ligand-induced Internalization of Human Neutrophil Chemokine Receptors CXCR1 and CXCR2

Rose¹,

Foley²,

Murphy

et al. 2004

Journal of Biological Chemistry

119

113

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It is well established that leukocyte chemotactic receptors, a subset of G protein-coupled receptors, undergo endocytosis after stimulation by ligand. However, the significance of this phenomenon to cell motility and other important leukocyte functions induced by chemoattractants has not been clearly defined. Here we show that in primary human neutrophils, the threshold levels of agonist required for endocytosis of the chemotactic receptors CXCR1 and CXCR2 were ϳ10-fold or higher than those needed for maximal chemotactic and calcium flux responses. Moreover, when stimulated by agonists at concentrations that are high enough for chemotaxis but too low for receptor endocytosis, neutrophil CXCR1 and CXCR2 could be reactivated in response to repeated application of the same agonist. Both receptors were excluded from Triton X-100-insoluble lipid rafts, and at high agonist concentrations were rapidly endocytosed by a clathrin/rab5/dynamin-dependent pathway. These data support the conclusion that neutrophil migration in response to CXCR1 or CXCR2 agonists is not dependent on endocytosis of CXCR1 or CXCR2. Rather than being integral to the process of cell migration, receptor endocytosis may be a terminal stop signal when cells reach the focus of inflammation where the chemoattractant concentrations are the highest.

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“…Phosphorylation of ITAMs results in activation of Syk family nonreceptor tyrosine kinases, which, in turn, activate several downstream effectors, including phosphatidylinositol 3-kinase (PI-3K) and phospholipase C␥ (12,13). Fc␥RIIIb is GPI-linked to the plasma membrane and is expressed at a 10-fold higher density than Fc␥RIIa (14). Because of the absence of transmembrane and cytoplasmic domains (15), it has been proposed that Fc␥RIIIb acts cooperatively with complement receptor 3 (CR3) in the activation of respiratory burst activity (16) or with Fc␥RIIa in mediating phagocytosis or respiratory burst activity (17)(18)(19).…”

mentioning

confidence: 99%

Differential Mitogen-Activated Protein Kinase Stimulation by Fcγ Receptor IIa and Fcγ Receptor IIIb Determines the Activation Phenotype of Human Neutrophils

Coxon¹,

Rane²,

Powell

et al. 2000

The Journal of Immunology

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FcγRs mediate immune complex-induced tissue injury. The hypothesis that FcγRIIa and FcγRIIIb control neutrophil responses by activating mitogen-activated protein kinases was examined. Homotypic and heterotypic cross-linking of FcγRIIa and/or FcγRIIIb resulted in a rapid, transient increase in ERK and p38 activity, with maximal stimulation between 1 and 3 min. FcγRIIa and FcγRIIIb stimulated distinct patterns of ERK and p38 activity, and heterotypic cross-linking failed to stimulate synergistic activation of either ERK or p38 activity. Both FcγRIIa and FcγRIIIb required activation of a nonreceptor tyrosine kinase and phosphatidylinositol 3-kinase for stimulation of ERK and p38. Inhibition of ERK activation with PD98059 enhanced H2O2 production stimulated by homotypic and heterotypic FcγR cross-linking. Inhibition of p38 with SB203580 attenuated H2O2 production stimulated by FcγRIIIb or heterotypic cross-linking, but had no effect on FcγRIIa-stimulated H2O2 production. On the other hand, PD98059 inhibited actin polymerization stimulated by FcγR cross-linking, while SB203580 had no effect. Inhibition of actin polymerization with cytochalasin D enhanced p38 activity stimulated by either FcγRIIa or FcγRIIIb, but cytochalasin D only enhanced H2O2 production stimulated by FcγRIIIb. Our data indicate that FcγRIIa and FcγRIIIb independently activate ERK and p38. The two receptors demonstrate different efficacies for ERK and p38 activation, and they do not act cooperatively. ERK and p38 provide stimulatory and inhibitory signals for neutrophil responses to immune complexes. In addition, these data indicate that actin reorganization may play a role in mediating p38-dependent activation of respiratory burst upon stimulation of FcγRIIIb in neutrophils.

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Function of human FcγRIIA and FcγRIIIB

Cited by 101 publications

References 61 publications

CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells

CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells

On the Mechanism and Significance of Ligand-induced Internalization of Human Neutrophil Chemokine Receptors CXCR1 and CXCR2

Differential Mitogen-Activated Protein Kinase Stimulation by Fcγ Receptor IIa and Fcγ Receptor IIIb Determines the Activation Phenotype of Human Neutrophils

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