Phospholipase Cγ/diacylglycerol-dependent activation of β2-chimaerin restricts EGF-induced Rac signaling

Wang, Hongbin; Yang, Chengfeng; Leskow, Federico Coluccio; Sun, Jing; Canagarajah, Bertram; Hurley, James H.; Kazanietz, Marcelo G.

doi:10.1038/sj.emboj.7601098

Cited by 51 publications

(98 citation statements)

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“…Furthermore, we could not see any translocation of α2-chimaerin upon treatment of cells with PMA although, in this case, β2-chimaerin did show an enrichment in the cellular membranes of Jurkat cells. This behavior is in contrast to previous results in this GAP family in other cell types [34,35,37]. Several observations indicate that the lack of regulation of chimaerin by DAG in Jurkat cells is not an experimental artifact.…”

Section: Discussioncontrasting

confidence: 56%

“…Previous works have shown that the upregulation of the activity of chimaerins during signal transduction occurs concurrently with their shuttling from the cytosol to either the Golgi apparatus or the plasma membrane. This translocation occurs through the binding of the chimaerin C1 domain to DAG and, in the case of the Golgi apparatus, on the additional binding of β2-chimaerin to the Golgi-localized Timp21-I protein [34,35,37]. To study whether a similar regulation occurred in T-cells, we monitored the changes in the subcellular localization of EGFP-tagged α2-and β□-chimaerin upon the treatment of Jurkat cells with anti-CD3 antibodies for 5 min.…”

Section: Chimaerin Proteins Do Not Translocate To the Plasma Membranementioning

confidence: 99%

“…All protein products of these genes are characterized by the presence of a C-terminal GAP catalytic domain and a most N-terminal C1 domain that binds diacylglycerol (DAG) and chemical analogs such as bryostatin or phorbol esters [27][28][29]32,33]. Previous studies have shown that the C1 domain is important for the subcellular localization of some of these family members [34,35]. The α2-and β2-family members have also an N-terminal SH2 domain involved, presumably, in heteromolecular interactions [31,[36][37][38].…”

Section: Introductionmentioning

confidence: 99%

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

Caloca

Delgado

Alarcón

et al. 2008

Cellular Signalling

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Chimaerins are GTPase-activating proteins that inactivate the GTP-hydrolase Rac1 in a diacylglycerol-dependent manner. To date, the study of chimaerins has been done mostly in neuronal cells. Here, we show that α2-and β2-chimaerin are expressed at different levels in T-cells and that they participate in T-cell receptor signaling. In agreement with this, we have observed that α2-and β2-chimaerins translocate to the T-cell/B-cell immune synapse and, using both gain-and loss-offunction approaches, demonstrated that their catalytic activity is important for the inhibition of the T-cell receptor-and Vav1-dependent stimulation of the transcriptional factor NF-AT. Mutagenesisbased approaches have revealed the molecular determinants that contribute to the biological program of chimaerins during T-cell responses. Unexpectedly, we have found that the translocation of chimaerins to the T-cell/B-cell immune synapse does not rely on the canonical binding of diacylglycerol to the C1 region of these GTPase-activating proteins. Taken together, these results identify chimaerins as candidates for the downmodulation of Rac1 in T-lymphocytes and, in addition, uncover a novel regulatory mechanism that mediates their activation in T-cells.

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Section: Discussioncontrasting

confidence: 56%

Section: Chimaerin Proteins Do Not Translocate To the Plasma Membranementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Caloca

Delgado

Alarcón

et al. 2008

Cellular Signalling

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“…Another possible effector of PLCc in RBL-2H3 cells is b2-chimaerin, which is a diacylglycerol-stimulated GTPaseactivating protein (GAP) specific for Rac [44]. A recent study in HeLa cells in fact has shown that activation of b-chimaerin inhibits EGF stimulation of Rac [45]. This mechanism could explain the effects of PLCc on Rac in mast cells.…”

Section: Discussionmentioning

confidence: 95%

Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

El‐Sibai

Backer

2006

Eur J Immunol

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The Rho GTPases Rac and Cdc42 play a central role in the regulation of secretory and cytoskeletal responses in antigen-stimulated mast cells. In this study, we examine the kinetics and mechanism of Rac and Cdc42 activation in the rat basophilic leukemia RBL-2H3 cells. The activation kinetics of both Rac and Cdc42 show a biphasic profile, consisting of an early transient peak at 1 min and a late sustained activation phase at 20-40 min. The inhibition of phospholipase C (PLC)c causes a twofold increase in Rac and Cdc42 activation that coincides with a dramatic production of atypical filopodialike structures. Inhibition of protein kinase C using bisindolylmaleimide mimics the effect of PLCc inhibition on Rac activation, but not on Cdc42 activation. In contrast, depletion of intracellular calcium leads to a complete inhibition of the early activation peak of both Rac and Cdc42, without significant effects on the late sustained activation. These data suggest that PLCc is involved in a negative feedback loop that leads to the inhibition of Rac and Cdc42. They also suggest that the presence of intracellular calcium is a prerequisite for both Rac and Cdc42 activation. IntroductionMast cells participate in the pathogenesis of immediate hypersensitivity and allergic reactions in humans [1]. Moreover, mast cells are important contributors to airway hyper-responsiveness that occurs in asthmatic inflammation [2]. In response to allergens and other exogenous stimuli, mast cells accumulate in the airway smooth muscle and in the bronchial intraepithelial layer [3]. The activation of mast cells, through the crosslinking of the FceRI, leads to the release of pre-formed early-phase inflammatory mediators and vasoactive substances from granules. It also leads to the in situ production of cytokines and bioactive lipids that contribute to the late-phase manifestation of the asthmatic reaction [4].Aggregation of FceRI on the surface of mast cells in response to multivalent ligand binding initiates a cascade of downstream signaling effectors that leads to degranulation [5]. These include phosphatidylinositol 3-kinase (PI3K), the guanine nucleotide exchange factor Vav, and phospholipase C (PLC)c1 [6]. The early activation of PLCc1 results in the generation of inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol. These two second messengers lead to increases in cytoplasmic calcium and activation of calcium/diacylglycerol-regulated isoforms of protein kinase C (PKC) which culminate in granule margination and exocytosis [7]. PI3K plays an important regulatory role as an upstream activator of PLCc1, as well as a regulator of calcium flux during mast cell degranulation [8][9][10][11][12][13].Members of the Rho family of small GTPases also regulate signaling events in mast cells [14][15][16]. In the rat basophilic leukemia (RBL-2H3) cells, Rac and Cdc42 have been implicated in the control of the FceRImediated phagocytosis and the regulation of migration, In conjunction with the secretory response, antigenstimulated mast cells undergo drama...

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“…DAG is a lipid second messenger produced at cell membranes from phosphatidylinositol 4,5-bisphosphate by members of the phospholipase C (PLC) family in response to a wide variety of stimuli. The C1 domain allows chimaerins to translocate to membranes in response to DAG signaling (6,16) and is likely to anchor them in close proximity to activated Rac.It is becoming clear that the SH2 domain is central to the regulation of ␣2-and ␤2-chimaerin activity, as under unstimulated conditions it folds over and occludes the C1 and GAP domains, auto-inhibiting the whole molecule (17-19). However, because ␣1-chimaerin lacks this SH2 domain, it is not clear how its activity is regulated.…”

mentioning

confidence: 99%

Rac GTPase-activating Protein (Rac GAP) α1-Chimaerin Undergoes Proteasomal Degradation and Is Stabilized by Diacylglycerol Signaling in Neurons

Marland

Pan

Buttery

2011

Journal of Biological Chemistry

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␣1-Chimaerin is a neuron-specific member of the Rho GTPase-activating protein family that selectively inactivates the small GTPase Rac. It is known to regulate the structure of dendrites and dendritic spines. We describe here that under basal conditions ␣1-chimaerin becomes polyubiquitinated and undergoes rapid proteasomal degradation. This degradation is partly dependent on the N-terminal region that is unique to this isoform. Mimicking diacylglycerol (DAG) signaling with a phorbol ester stabilizes endogenous ␣1-chimaerin against degradation and causes accumulation of the protein. The stabilization requires phorbol ester binding via the C1 domain of the protein and is independent of PKC activity. In addition, overexpression of a constitutively active Rac1 mutant is sufficient to cause an accumulation of ␣1-chimaerin through a phospholipase C-dependent mechanism, showing that endogenous DAG signaling can also stabilize the protein. These results suggest that signaling via DAG may regulate the abundance of ␣1-chimaerin under physiological conditions, providing a new model for understanding how its activity could be controlled.Dendritic spines are the post-synaptic component of most excitatory synapses in the central nervous system and exhibit a large degree of structural plasticity (1). The actin cytoskeleton is highly enriched within spines, acting both as a structural support and driver of morphological change (2). Members of the Rho small GTPase family control the dynamics of actin through a complex set of downstream effectors (3), and in neurons the family member Rac1 is closely involved in regulating spine structure and density (4, 5).Two groups of proteins have important roles in Rho GTPase regulation; their signaling is activated by guanine nucleotide exchange factors, which promote formation of the active GTP-bound form, whereas GTPase-activating proteins (GAPs) 2 increase the level of the inactive GDP-bound form by accelerating hydrolysis of GTP (3). In previous work, we found that the neuron-specific Rac GAP ␣1-chimaerin regulates spine and dendrite morphology through a mechanism that depends on its GAP activity. We showed that overexpression of ␣1-chimaerin in neurons causes spine pruning, whereas knockdown promotes overgrowth of atypical spines and filopodia from dendrites (6). These effects suggest ␣1-chimaerin has a role in the maintenance of normal spine structure.Vertebrate genomes contain two chimaerin genes: CHN1 encodes the ␣-chimaerins, and CHN2 encodes the ␤-chimaerins, with each gene giving rise to two alternative transcripts that are translated into proteins differing at their N termini (7). ␣1-and ␤1-chimaerin have a relatively short N-terminal region that does not encode any recognizable domains, whereas ␣2-and ␤2-chimaerin both include a functional SH2 domain that can bind to phosphotyrosine motifs within receptors such as EphA4 (8 -12). All chimaerin isoforms contain a GAP domain with specificity in vitro for Rac1 (13,14), and they are unique among other Rho GAPs because they also conta...

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Phospholipase Cγ/diacylglycerol-dependent activation of β2-chimaerin restricts EGF-induced Rac signaling

Cited by 51 publications

References 35 publications

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

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

Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

Rac GTPase-activating Protein (Rac GAP) α1-Chimaerin Undergoes Proteasomal Degradation and Is Stabilized by Diacylglycerol Signaling in Neurons

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