Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3

Teixeira, Christine; Stang, Stacey L.; Zheng, Yong; Beswick, N.; Stone, James C.

doi:10.1182/blood-2002-11-3621

Cited by 118 publications

(129 citation statements)

References 34 publications

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“…PKCy expression was described initially in T and myogenic cells (Baier et al, 1993;Chang et al, 1993), but can be expressed at even higher levels in GIST (Allander et al, 2001;Nielsen et al, 2002;Duensing et al, 2004a;Medeiros et al, 2004). PKCy is a calcium-independent but phospholipid-dependent dual-specificity kinase, which is activated by the second messenger diacylglycerol (Teixeira et al, 2003). PKCy biologic roles have been evaluated extensively in T cells, where PKCy regulates interleukin-2 production and CD25 expression by activating nuclear factor-kB (NFkB) and activator protein-1 (Sun et al, 2000;Bi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Zhu

Demetri

et al. 2008

Oncogene

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Section: Introductionmentioning

confidence: 99%

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Zhu

Demetri

et al. 2008

Oncogene

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“…RasGRPs were initially identified in neuronal tissues (46), but members of this family of Ras nucleotide exchange factors were subsequently shown to be expressed and functionally relevant in immune cells (23,25,26,47). Indeed, interference with DAG metabolism in T cells alters Ras signaling, presumably by modulation of RasGRP activity (48,49).…”

Section: Discussionmentioning

confidence: 99%

“…Mouse anti-T7 antibody was from Novagen. Rabbit anti-RasGRP3 antibodies were previously characterized (26). Polyclonal Rap1 antibodies were from Santa Cruz Biotechnology (Krev-1).…”

Section: Methodsmentioning

confidence: 99%

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Localized Diacylglycerol-dependent Stimulation of Ras and Rap1 during Phagocytosis

Botelho

Harrison

Stone

et al. 2009

Journal of Biological Chemistry

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We describe a role for diacylglycerol in the activation of Ras and Rap1 at the phagosomal membrane. During phagocytosis, Ras density was similar on the surface and invaginating areas of the membrane, but activation was detectable only in the latter and in sealed phagosomes. Ras activation was associated with the recruitment of RasGRP3, a diacylglycerol-dependent Ras/ Rap1 exchange factor. Recruitment to phagosomes of RasGRP3, which contains a C1 domain, parallels and appears to be due to the formation of diacylglycerol. Accordingly, Ras and Rap1 activation was precluded by antagonists of phospholipase C and of diacylglycerol binding. Ras is dispensable for phagocytosis but controls activation of extracellular signal-regulated kinase, which is partially impeded by diacylglycerol inhibitors. By contrast, cross-activation of complement receptors by stimulation of Fc␥ receptors requires Rap1 and involves diacylglycerol. We suggest a role for diacylglycerol-dependent exchange factors in the activation of Ras and Rap1, which govern distinct processes induced by Fc␥ receptor-mediated phagocytosis to enhance the innate immune response.Receptors that interact with the constant region of IgG (Fc␥R) 4 mediate the recognition and elimination of soluble immune complexes and particles coated (opsonized) with immunoglobulins. Clustering of Fc␥R on the surface of leukocytes upon attachment to multivalent ligands induces their activation and subsequent internalization. Soluble immune complexes are internalized by endocytosis, a clathrin-and ubiquitylation-dependent process (1). In contrast, large, particulate complexes like IgG-coated pathogens are ingested by phagocytosis, a process that is contingent on extensive actin polymerization that drives the extension of pseudopods (2). In parallel with the internalization of the opsonized targets, crosslinking of phagocytic receptors triggers a variety of other responses that are essential components of the innate immune response. These include degranulation, activation of the respiratory burst, and the synthesis and release of multiple inflammatory agents (3, 4).Like T and B cell receptors, Fc␥R possesses an immunoreceptor tyrosine-based activation motif that is critical for signal transduction (3, 4). Upon receptor clustering, tyrosyl residues of the immunoreceptor tyrosine-based activation motif are phosphorylated by Src family kinases, thereby generating a docking site for Syk, a tyrosine kinase of the ZAP70 family (3, 4). The recruitment and activation of Syk in turn initiates a cascade of events that include activation of Tec family kinases, Rho-and ARF-family GTPases, phosphatidylinositol 3-kinase, phospholipase C␥ (PLC␥), and a multitude of additional effectors that together remodel the underlying cytoskeleton, culminating in internalization of the bound particle (5, 6).Phosphoinositide metabolism is thought to be critical for Fc␥R-induced phagocytosis (7,8). Highly localized and very dynamic phosphoinositide changes have been observed at sites of phagocytosis: phosphatidyli...

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“…Although RasGRP1 is very important in T cells, RasGRP2 has been shown to be critical in platelet activation (8,9). On the other hand, RasGRP3 is preferentially expressed in B cells and is required for optimal activation of Erk upon B cell receptor (BCR) crosslinking (10,11).…”

Section: Ras Guanine Nucleotide-releasing Protein (Rasgrp)mentioning

confidence: 99%

The Role of Ras Guanine Nucleotide Releasing Protein 4 in FcϵRI-mediated Signaling, Mast Cell Function, and T Cell Development

Zhu

Fuller

Zhang

2012

Journal of Biological Chemistry

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Background: RasGRP4 is one member of the RasGRP family and is highly expressed in mast cells. Results: Fc⑀RI signaling, mast cell function, and thymocyte development are severely impaired by RasGRP1 and RasGRP4 deficiency. Conclusion: This study indicated that the RasGRP family is important in mast cells and T cells.Significance: This work demonstrates immune cells employ multiple members of the RasGRP family to activate the Ras-Erk pathway.

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Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3

Abstract: Members of the

Cited by 118 publications

References 34 publications

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Localized Diacylglycerol-dependent Stimulation of Ras and Rap1 during Phagocytosis

The Role of Ras Guanine Nucleotide Releasing Protein 4 in FcϵRI-mediated Signaling, Mast Cell Function, and T Cell Development

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