Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling

Caloca, Marı́a J.; Delgado, Pilar; Alarcón, Balbino; Bustelo, Xosé R.

doi:10.1016/j.cellsig.2007.12.015

Cited by 26 publications

(25 citation statements)

References 57 publications

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“…Using luciferase reporter assays, we first examined the effect of WT ␤2-chimaerin and the Y153F mutant on NF-AT activity. As reported previously (25), ␤2-chimaerin overexpression clearly reduced NF-AT activity after stimulation of Jurkat T cells with anti-CD3 or -CD3/CD28 Ab (Fig. 3B).…”

Section: Tcr Triggering Induces Tyr Phosphorylation Of ␤2-chimaerin-␤supporting

confidence: 64%

“…, where it is proposed to regulate Rac activation during T cell synapse formation (25). Moreover, a recent study using COS-1 cells showed that Src-dependent tyrosine phosphorylation negatively regulates ␤2-chimaerin Rac-GAP functions (31).…”

Section: Tcr Triggering Induces Tyr Phosphorylation Of ␤2-chimaerin-␤mentioning

confidence: 99%

“…Experiments in T cells showed that ␤2-chimaerin participates in chemokine-dependent regulation of T cell migration and adhesion (24). A very recent study implicates chimaerins in the modulation of Rac activity during T cell synapse formation, suggesting that this protein family contributes to DAG-mediated regulation of cytoskeletal remodeling during T cell activation (25).…”

mentioning

confidence: 99%

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T Cell Receptor-dependent Tyrosine Phosphorylation of β2-Chimaerin Modulates Its Rac-GAP Function in T Cells

Siliceo

Mérida

2009

Journal of Biological Chemistry

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The actin cytoskeleton has an important role in the organization and function of the immune synapse during antigen recognition. Dynamic rearrangement of the actin cytoskeleton in response to T cell receptor (TCR) triggering requires the coordinated activation of Rho family GTPases that cycle between active and inactive conformations. This is controlled by GTPase-activating proteins (GAP), which regulate inactivation of Rho GTPases, and guanine exchange factors, which mediate their activation. Whereas much attention has centered on guanine exchange factors for Rho GTPases in T cell activation, the identity and functional roles of the GAP in this process are largely unknown. We previously reported ␤2-chimaerin as a diacylglycerol-regulated Rac-GAP that is expressed in T cells. We now demonstrate Lck-dependent phosphorylation of ␤2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of ␤2-chimaerin, decreasing its GAP activity to Rac. This study establishes the existence of TCR-dependent regulation of ␤2-chimaerin and identifies a novel mechanism for its inactivation.T cell activation requires presentation of an antigen by antigen-presenting cells (APC) 2 to the T cell receptor (TCR); this event involves the reorganization of several scaffolds and signaling proteins, leading to formation of the immunological synapse (IS) (1). Correct protein redistribution during synapse formation is critical for an efficient T cell response, and it is largely regulated by actin polymerization at the T cell/APC contact site as a result of TCR-regulated Rac-dependent signals (2, 3). Like other Rho GTPases, Rac cycles between a GTP-bound active state and a GDP-bound inactive state. This continuous recycling is regulated by the concerted action of two proteins as follows: GEF, which activates Rac by mediating GDP/GTP exchange (4), and GAP, which induces Rac inactivation by accelerating intrinsic Rac GTPase activity, converting GTP to GDP (5).Vav-1 is the best studied GEF for Rac, and it has critical roles in T cell-dependent functions (6). In naive, unstimulated T cells, Vav-1 is in an inactive state through autoinhibition, as the GEF domain is blocked by the N-terminal region (7). This autoinhibition is relieved by TCR-mediated tyrosine phosphorylation (8, 9). Thymocytes from Vav-1-deficient mice have a developmental block, and their mature T cells show severe defects in IS formation, as well as reduced Ca 2ϩ influx, IL-2 production, T cell proliferation, and cytotoxic activity (10 -13). Although several studies have shown a key role for Vav-1, the mechanisms that govern Rac inactivation downstream of the TCR remain elusive.The chimaerins are a family of Rho-GAP, with specific activity for Rac. In addition to their catalytic domain, they have an N-terminal SH2 domain and a C1 domain required for interaction with the lipid messenger diacylglycerol (DAG) and with phorbol esters (14). There are two mammal...

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Section: Tcr Triggering Induces Tyr Phosphorylation Of ␤2-chimaerin-␤supporting

confidence: 64%

Section: Tcr Triggering Induces Tyr Phosphorylation Of ␤2-chimaerin-␤mentioning

confidence: 99%

mentioning

confidence: 99%

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T Cell Receptor-dependent Tyrosine Phosphorylation of β2-Chimaerin Modulates Its Rac-GAP Function in T Cells

Siliceo

Mérida

2009

Journal of Biological Chemistry

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“…9). Likewise, chimaerins, a group of DAGdependent Rac1 GTPase-activating proteins, have been shown to inhibit Vav-mediated responses in T-lymphocytes (54).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Analysis of the Amplification and Diversification Events Induced by Vav Proteins in B-lymphocytes

Caloca

Zugaza²,

Bustelo³

2008

Journal of Biological Chemistry

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“…It has been reported that T cell receptor engagement by antigen promotes the rapid activation of these GTPases together with an array of other signaling molecules (12,13). Subsequently, Rac proteins transduce signals through intermediate signaling molecules, most notably PKC (14), phosphatidylinositol 3-kinase (PI3K) (5), calcium (15), and PLC␥1 (13). Importantly, Rac1 controls the translocation of RasGRP1 (a guanine nucleotide exchange factor for Ras) to the actin juxtamembrane structures to facilitate Ras/ERK pathway activation (12).…”

mentioning

confidence: 99%

Rac1 Protein Regulates Glycogen Phosphorylase Activation and Controls Interleukin (IL)-2-dependent T Cell Proliferation

Arrizabalaga

Lacerda

Zubiaga

et al. 2012

Journal of Biological Chemistry

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Background: Rac1 has a relevant role in signal transduction pathways in T lymphocytes. Results: Rac1 GTPase associates with glycogen phosphorylase and modulates its enzymatic activity to trigger T cell proliferation. Conclusion: This study reveals a new role for Rac1 GTPase in cellular physiology, coordinating metabolism and proliferation. Significance: This new Rac1/PYGM pathway might be essential for an appropriate immune response.

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Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling

Cited by 26 publications

References 57 publications

T Cell Receptor-dependent Tyrosine Phosphorylation of β2-Chimaerin Modulates Its Rac-GAP Function in T Cells

T Cell Receptor-dependent Tyrosine Phosphorylation of β2-Chimaerin Modulates Its Rac-GAP Function in T Cells

Mechanistic Analysis of the Amplification and Diversification Events Induced by Vav Proteins in B-lymphocytes

Rac1 Protein Regulates Glycogen Phosphorylase Activation and Controls Interleukin (IL)-2-dependent T Cell Proliferation

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