Rac-1 Regulates Nuclear Factor of Activated T Cells (NFAT) C1 Nuclear Translocation in Response to Fcε Receptor Type 1 Stimulation of Mast Cells

Turner, Helen; Gómez, Manuel; McKenzie, Edward A.; Kirchem, Antje; Lennard, Andrew; Cantrell, Doreen A.

doi:10.1084/jem.188.3.527

Cited by 48 publications

(36 citation statements)

References 33 publications

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“…Although it could involve increased nuclear translocation of NF-AT, as suggested by studies of Rac function in mast cell (17), it is clear from our studies that a GEF-independent function, and presumably Rac-independent function, of Vav1 can contribute to NF-AT regulation. This is not a surprising finding given the multiple protein interaction domains, besides the GEF domain, present in Vav1.…”

Section: Discussionmentioning

confidence: 79%

“…However, the effects of its GEF activity on Rac or Rho have been implicated based on studies of Vav1-deficient cells (6,8). Similarly, Rac activation has been implicated in NF-AT-mediated activation in response to Fc⑀RI stimulation in mast cells (17). Collectively, these data would suggest the following model.…”

Section: Engagement Of the T Cell Antigen Receptor (Tcr)mentioning

confidence: 75%

“…Rac is one target of Vav GEF function, and it has been implicated in the activation of NF-AT in T cells yet is not enough to induce NF-AT-driven transcription (6). Moreover, it has been reported that GTPbound-Rac or a mutant form of Rac that cannot hydrolyze GTP, RacV12, is sufficient to induce translocation of NF-AT from the cytoplasm to the nucleus yet is not enough to induce NF-ATdriven transcription (17). This prompted us to determine whether GEF activity of Vav1 is essential for its role in potentiating NF-AT in Jurkat cells.…”

Section: Discussionmentioning

confidence: 99%

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A Guanine Nucleotide Exchange Factor-independent Function of Vav1 in Transcriptional Activation

Kuhne

Weiss

2000

Journal of Biological Chemistry

104

110

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T cell antigen receptor (TCR) stimulation induces the tyrosine phosphorylation of several intracellular proteins including the protooncogene Vav1. Vav1 expression is necessary for normal T cell development and activation. We previously showed that overexpression of Vav1 in Jurkat T cells potentiates the activity of the transcription factor nuclear factor of activated T cells (NF-AT). The mechanism by which Vav1 participates in TCR signaling events is not clear. Vav1 contains a guanine nucleotide exchange factor (GEF) domain that has specificity for Rac and other Rho GTPases that have been recently implicated in T cell activation events. Significantly, in vitro tyrosine phosphoryation of Vav1 by Lck activates its exchange activity. This Lck-mediated phosphorylation of Vav1 has been reported to depend upon Tyr-174 in Vav1, a site implicated in Vav1 function by other studies as well. In this report, we demonstrated that Tyr-174 is not required for the TCR-induced phosphorylation of Vav1 in vivo. Moreover, mutation of Tyr-174 augmented the ability of Vav1 to up-regulate NF-AT activation as well as the Vav1 GEF function leading to Rac activation. However, we also showed that the GEF activity of Vav1 was neither sufficient nor necessary for potentiation of NF-AT, and thereby we identify a GEFindependent role of Vav1 in potentiating NF-AT-driven transcription. Oncogenic Vav1 in which the amino-terminal 67 amino acids were deleted had elevated GEF activity but did not potentiate NF-AT when overexpressed in Jurkat cells. We also showed that a GEF mutant form of Vav1 that had impaired GEF function could still potentiate NF-AT. These studies reveal a previously unrecognized negative regulatory function of Tyr-174 in Vav1 and suggest that domains other than the Vav1 GEF domain contribute to TCR signals leading to NF-AT activation. Engagement of the T cell antigen receptor (TCR)1 with antigen or with cross-linking antibodies initiates a signaling cascade that leads to activation of the T cell. One of the proximal events triggered by TCR engagement is the activation of protein-tyrosine kinases, which results in the tyrosine phosphorylation of several substrates. Previous work has demonstrated that activation of the Src tyrosine kinase Lck is necessary to initiate the signaling cascade. Lck is required to phosphorylate the cytoplasmic tails of the CD3 complex (␥␦⑀) and the chain of the TCR on tyrosines within motifs designated as immunoreceptor tyrosine-based activation motifs (ITAMs). Phosphorylation of the ITAMs provides docking sites for the Src homology-2 (SH2) domains of the Syk family protein-tyrosine kinases, ZAP-70, and Syk. Recruitment of ZAP-70 or Syk to the phosphorylated ITAMs leads to the activation of these proteintyrosine kinases and subsequent tyrosine phosphorylation of multiple intracellular substrates.One substrate that is rapidly tyrosine-phosphorylated in response to TCR engagement is the 95-kDa protooncogene Vav1. Vav1 is expressed exclusively in hematopoietic cells. However, a homologous protein, Vav2, i...

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Section: Discussionmentioning

confidence: 79%

Section: Engagement Of the T Cell Antigen Receptor (Tcr)mentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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A Guanine Nucleotide Exchange Factor-independent Function of Vav1 in Transcriptional Activation

Kuhne

Weiss

2000

Journal of Biological Chemistry

104

110

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“…Coexpression of an activated form of calcineurin or treatment with calcium ionophores appears however to synergize with a Ras signal to produce full NFAT activation (31)(32)(33)(34). In both T cells and other immune cells a role for Rac proteins has also been demonstrated with experiments demonstrating that a dominant negative form of Rac can inhibit NFAT activation (35,36). The activation of NFAT3 in cardiac myocytes therefore appears to differ in significant fashion from immune cells.…”

Section: Discussionmentioning

confidence: 96%

Ras Regulates NFAT3 Activity in Cardiac Myocytes

Ichida

Finkel

2001

Journal of Biological Chemistry

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“…7, recombinant RasGRP4 is indeed able to activate H-Ras in vitro. MCs express varied members of the Ras superfamily of GTP-binding proteins (12,26,(42)(43)(44)(45)(46)(47). However, because recombinant hRasGRP3 is able to transfer GTP to GDP-loaded H-Ras, R-Ras, and Rap1 in vitro (18), it remains to be determined which Ras family members RasGRP4 prefers to interact with inside a living MC.…”

Section: Rasgrp4mentioning

confidence: 99%

RasGRP4, a New Mast Cell-restricted Ras Guanine Nucleotide-releasing Protein with Calcium- and Diacylglycerol-binding Motifs

Yang¹,

Li²,

Wong³

et al. 2002

Journal of Biological Chemistry

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A cDNA was isolated from interleukin 3-developed, mouse bone marrow-derived mast cells (MCs) that contained an insert (designated mRasGRP4) that had not been identified in any species at the gene, mRNA, or protein level. By using a homology-based cloning approach, the ϳ2.6-kb hRasGRP4 transcript was also isolated from the mononuclear progenitors residing in the peripheral blood of normal individuals. This transcript information was then used to locate the RasGRP4 gene in the mouse and human genomes, to deduce its exon/ intron organization, and then to identify 10 single nucleotide polymorphisms in the human gene that result in 5 amino acid differences. The >15-kb hRasGRP4 gene consists of 18 exons and resides on a region of chromosome 19q13.1 that had not been sequenced by the Human Genome Project. Human and mouse MCs and their progenitors selectively express RasGRP4, and this new intracellular protein contains all of the domains present in the RasGRP family of guanine nucleotide exchange factors even though it is <50% identical to its closest homolog. Recombinant RasGRP4 can activate H-Ras in a cation-dependent manner. Transfection experiments also suggest that RasGRP4 is a diacylglycerol/phorbol ester receptor. Transcript analysis of an asthma patient, a mastocytosis patient, and the HMC-1 cell line derived from a MC leukemia patient revealed the presence of substantial amounts of non-functional forms of hRas-GRP4 due to an inability to remove intron 5 in the precursor transcript. Because only abnormal forms of hRas-GRP4 were identified in the HMC-1 cell line, this immature MC progenitor was used to address the function of RasGRP4 in MCs. HMC-1 leukemia cells differentiated and underwent granule maturation when induced to express a normal form of RasGRP4. Thus, RasGRP4 plays an important role in the final stages of MC development.

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Rac-1 Regulates Nuclear Factor of Activated T Cells (NFAT) C1 Nuclear Translocation in Response to Fcε Receptor Type 1 Stimulation of Mast Cells

Cited by 48 publications

References 33 publications

A Guanine Nucleotide Exchange Factor-independent Function of Vav1 in Transcriptional Activation

A Guanine Nucleotide Exchange Factor-independent Function of Vav1 in Transcriptional Activation

Ras Regulates NFAT3 Activity in Cardiac Myocytes

RasGRP4, a New Mast Cell-restricted Ras Guanine Nucleotide-releasing Protein with Calcium- and Diacylglycerol-binding Motifs

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