Activation of Protein Kinase C βII by the Stereo-specific Phosphatidylserine Receptor Is Required for Phagocytosis of Apoptotic Thymocytes by Resident Murine Tissue Macrophages

Todt, Jill C.; Hu, Bin; Punturieri, Antonello; Sonstein, Joanne; Polak, Timothy; Curtis, Jeffrey L.

doi:10.1074/jbc.m202967200

Cited by 30 publications

(35 citation statements)

References 84 publications

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“…Thus, although initial adhesion must constitute an obligatory step in phagocytosis, adhesion itself did not appear to be the rate-limiting step in the process for the majority of AMø that do bind apoptotic thymocytes. Why many of the remaining AMø that bind apoptotic cells do not go on to ingest any is uncertain, although post-receptor defects in signal transduction, such as the markedly reduced expression of PKC βII in murine AMø (14), probably contribute.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently shown that both AMø and PMø express PS-R, and that mAb 217 against the PS-R has no effect on adhesion of apoptotic cells to either AMø or PMø, yet profoundly inhibits phagocytosis by both types of Mø (14). However, because receptors other the PS-R can also bind PS in a stereo-nonspecific fashion, we next used annexin V to examine the importance of PS-binding in adhesion in this assay.…”

Section: Mertk Is Dispensable For Apoptotic Cell Adhesion In Vitromentioning

confidence: 99%

“…More recently, we showed that both types of Mø express the stereospecific receptor for phosphatidylserine (PS-R) (13), and that mAb against PS-R profoundly inhibited phagocytosis but not adhesion of apoptotic cells by both AMø and PMø (14). We also found that at least a portion of the decreased ingestion of apoptotic cells by murine AMø can be attributed to markedly decreased expression of protein kinase C isoform beta II, which we proved to be uniquely required for this process in both types of Mø (14). However, it remained uncertain whether this difference was the sole explanation of the AMø functional deficiency.…”

Section: Introductionmentioning

confidence: 99%

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Resident Murine Alveolar and Peritoneal Macrophages Differ in Adhesion of Apoptotic Thymocytes

Jennings²,

Sonstein³

et al. 2004

Am J Respir Cell Mol Biol

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Apoptotic cells must be cleared efficiently by macrophages (Mø) to prevent autoimmunity, yet their ingestion impairs Mø microbicidal function. The principal murine resident lung phagocyte, the alveolar Mø (AMø), is specifically deficient at apoptotic cell ingestion, both in vitro and in vivo, compared to resident peritoneal Mø (PMø). To further characterize this deficiency, we assayed static adhesion in vitro using apoptotic thymocytes and resident AMø and PMø from normal C57BL/6 mice. Adhesion of apoptotic thymocytes by both types of Mø was rapid, specific, and cold-sensitive. Antibody against the receptor tyrosine kinase MerTK (Tyro12) blocked phagocytosis but not adhesion in both types of Mø. Surfactant protein A increased adhesion and phagocytosis by AMø, but not to the levels seen using PMø. Adhesion was largely cationindependent for PMø and calcium-dependent for AMø. Adhesion was not inhibited in either Mø type by mAbs against β1 or β3 integrins or scavenger receptor I/II (CD204), but AMø adhesion was inhibited by specific mAbs against CD11c/CD18. Thus, resident murine tissue Mø from different tissues depend on qualitatively disparate receptors systems to bind apoptotic cells. The decreased capacity of murine AMø to ingest apoptotic cells is only partially explained by reduced initial adhesion.

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Section: Discussionmentioning

confidence: 99%

Section: Mertk Is Dispensable For Apoptotic Cell Adhesion In Vitromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Resident Murine Alveolar and Peritoneal Macrophages Differ in Adhesion of Apoptotic Thymocytes

Jennings²,

Sonstein³

et al. 2004

Am J Respir Cell Mol Biol

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“…Upon exposure of macrophages to apoptotic cells, PLCγ2 associates with Mer and becomes phosphorylated . PLC can activate classical protein kinase Cs (PKCs) such as PKC βII, which is required for PS receptor-dependent phagocytosis in macrophages (Todt et al, 2002). In addition, the Gas6-Mer system may also cooperate with the soluble bridging molecule milk fat globule-EGF factor 8 protein (MFG-E8) and its receptor αvβ5 integrin to stimulate the lamellipodia formation necessary for phagocytic engulfment of apoptotic cells.…”

Section: Mer Signaling-much Of the Evidence Delineating Mer Signalingmentioning

confidence: 99%

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Linger¹,

Keating²,

Earp

et al. 2008

Advances in Cancer Research

632

688

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Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and down-stream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are over-expressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer.

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“…Liu et al demonstrated that azoxymethane-induced colon carcinogenesis was abolished in PKC␤ KO mice and that transduction of PKC␤II can restore its susceptibility (32). Todt et al (33) suggested that PKC␤II is involved in phagocytosis of apoptic cells by murine peritoneal macrophages with pharmacological approaches. We revealed in this study that PKC␤ isoforms are specifically exploited in the Fc⑀RI-mediated signal transduction in mast cells.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Protein Kinase C βII in Activation of Mast Cells by Monomeric IgE

Liu

Furuta

Teshima

et al. 2005

Journal of Biological Chemistry

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Accumulating evidence suggests that IgE-mediated activation of mast cells occurs even in the absence of antigen, which is referred to as "monomeric IgE" responses. Although monomeric IgE was found to induce a wide variety of responses, such as up-regulation of the Fc⑀RI, survival, cytokine production, histamine synthesis, and adhesion to fibronectin, it remains to be clarified how mast cells are activated in the absence of antigen. It has been controversial whether monomeric IgE responses are mediated by a similar signaling mechanism to antigen stimulation, although recent studies suggest that IgE can induce the Fc⑀RI aggregation even in the absence of antigen. In this study, we focused on the role of conventional protein kinase C (cPKC), since this response is suppressed by a specific inhibitor for cPKC. Monomeric IgE-induced Ca 2؉ influx was not observed in a mouse mastocytoma cell line, which lacks the expression of PKC␤II, although Ca 2؉ influx induced by cross-linking of the Fc⑀RI was intact. Transfection of PKC␤II cDNA was found to restore the Ca 2؉ influx induced by monomeric IgE in this cell line. Furthermore, the dominant negative form of PKC␤II (PKC␤II/T500V) significantly suppressed the Ca 2؉ influx, histamine synthesis, and interleukin-6 production in another mouse mast cell line, which is highly sensitive to monomeric IgE. Expression of PKC␤II/T500V was found not to affect the antigen-induced responses. These results suggest that PKC␤II plays a critical role in monomeric IgE responses, but not in antigen responses.Activation of mast cells triggers allergic and inflammatory responses through the release of a wide variety of mediators, such as histamine, arachidonic acid metabolites, and neutral proteases, and modulates immune responses through the production of cytokines and chemokines (1, 2). One of the prominent mechanisms for activation of mast cells is cross-linking of the Fc⑀RI, the high affinity receptor for IgE, by the multivalent antigen, and various signaling molecules have been identified in this pathway (3, 4). Furthermore, accumulating evidence has indicated that IgE-mediated activation of mast cells can occur even in the absence of the multivalent antigen (5). Sensitization of IL-3 2 -dependent mouse bone marrow-derived mast cells (BMMCs) with IgE induces an array of events, such as up-regulation of the Fc⑀RI (6, 7), resistance to apoptosis under IL-3 deprivation (8 -11), cytokine production (9, 10), histamine synthesis (12), and adhesion to fibronectin (13,14). These results have clearly indicated that sensitization with IgE (monomeric IgE) is able to activate mast cells in the absence of antigen. However, it remains to be clarified as to how monomeric IgE activates mast cells and what kinds of signaling molecules are involved in this pathway.Some preceding studies revealed that signaling molecules are shared between monomeric IgE responses and responses induced by crosslinking with multivalent antigen; weak but sustained tyrosine phosphorylation of several signaling components, which a...

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Activation of Protein Kinase C βII by the Stereo-specific Phosphatidylserine Receptor Is Required for Phagocytosis of Apoptotic Thymocytes by Resident Murine Tissue Macrophages

Cited by 30 publications

References 84 publications

Resident Murine Alveolar and Peritoneal Macrophages Differ in Adhesion of Apoptotic Thymocytes

Resident Murine Alveolar and Peritoneal Macrophages Differ in Adhesion of Apoptotic Thymocytes

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Critical Role of Protein Kinase C βII in Activation of Mast Cells by Monomeric IgE

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