Diacylglycerol Kinase ζ Regulates Actin Cytoskeleton Reorganization through Dissociation of Rac1 from RhoGDI

Abramovici, Hanan; Mojtabaie, Parmiss; Parks, Robin J.; Zhong, Xiaomei; Koretzky, Gary A.; Topham, Matthew K.; Gee, Stephen H.

doi:10.1091/mbc.e07-12-1248

Cited by 73 publications

(107 citation statements)

References 72 publications

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“…During hepatocyte growth factor-mediated membrane ruffling in Madin-Darby canine kidney cells, diacylglycerol kinase (DGK)a promoted the translocation of atypical protein kinase Cz/i, stably associated with the RhoGDIa-Rac1 complex, to the PM through PA production (31). Additionally, it was reported that DGKz, stably associated with PAK1 and RhoGDIa-Rac1, promoted the release of RhoGDIa from Rac1 through DGKz→PA→PAK1-mediated RhoGDIa phosphorylation at platelet-derived growth factor-induced membrane ruffling in fibroblasts (32). These studies support an involvement of PA produced from DGK in regulation of RhoGDIa-Rac1 translocation to membranes and dissociation on membranes.…”

Section: Discussionsupporting

confidence: 53%

Negative Charges in the Flexible N-Terminal Domain of Rho GDP-Dissociation Inhibitors (RhoGDIs) Regulate the Targeting of the RhoGDI–Rac1 Complex to Membranes

Ueyama

Son

Kobayashi

et al. 2013

The Journal of Immunology

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In its resting state, Rho GDP-dissociation inhibitor (RhoGDI) α forms a soluble cytoplasmic heterodimer with the GDP-bound form of Rac. Upon stimulation, the dissociation of RhoGDIα from the RhoGDIα–Rac complex is a mandatory step for Rac activation; however, this mechanism is poorly understood. In this study, we examined how the cytoplasm/membrane cycles of the RhoGDI–Rac complex are regulated, as well as where RhoGDI dissociates from the RhoGDI–Rac complex, during FcγR-mediated phagocytosis. The negatively charged and flexible N terminus (25 residues) of RhoGDIα, particularly its second negative amino acid cluster possessing five negatively charged amino acids, was a pivotal regulator in the cytoplasm/membrane cycles of the RhoGDI–Rac complex. We also found that RhoGDIα translocated to the phagosomes as a RhoGDIα–Rac1 complex, and this translocation was mediated by an interaction between the polybasic motif in the C terminus of Rac1 and anionic phospholipids produced on phagosomes, such as phosphatidic acid, that is, by a phagosome-targeting mechanism of Rac1. Thus, we demonstrated that the targeting/accumulation of the RhoGDIα–Rac1 complex to phagosomes is regulated by a balance between three factors: 1) the negatively charged and flexible N-terminal of RhoGDIα, 2) the binding affinity of RhoGDIα for Rac1, and 3) anionic phospholipids produced on phagosomes. Moreover, we demonstrated that the mechanism of targeting/accumulation of the RhoGDIα–Rac1 complex is also applicable for the RhoGDIβ-Rac1 complex.

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Section: Discussionsupporting

confidence: 53%

Negative Charges in the Flexible N-Terminal Domain of Rho GDP-Dissociation Inhibitors (RhoGDIs) Regulate the Targeting of the RhoGDI–Rac1 Complex to Membranes

Ueyama

Son

Kobayashi

et al. 2013

The Journal of Immunology

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“…EGFR activation is known to activate PLD and enhance phosphatidic acid levels in membrane microdomains (31). It is worth noting that both the F-BAR/FX of Fer and the poly-basic C domain of Rac1 bind to phosphatidic acid, leading to Fer activation and reduced Rac1 sequestration by RhoGDIa (11), (38), (39). Fer can also phosphorylate RhoGDIa directly to limit Rac1 binding (22).…”

Section: Discussionmentioning

confidence: 99%

Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis

Ahn

Truesdell

Meens

et al. 2013

Molecular Cancer Research

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Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non–small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis. Implications: Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952–63. ©2013 AACR.

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“…Recently, DGKζ was shown to regulate PAK1-mediated phosphorylation of RhoGDI, leading to selective activation of Rac but not of Cdc42 (30). Conversely, PKCζ-dependent phosphorylation of RhoGDI promotes the release of both Rac and Cdc42 (21).…”

Section: Discussionmentioning

confidence: 99%

Diacylglycerol kinase α mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI

Chianale

Rainero

Cianflone

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Diacylglycerol kinases (DGKs) convert diacylglycerol (DAG) into phosphatidic acid (PA), acting as molecular switches between DAG-and PA-mediated signaling. We previously showed that Srcdependent activation and plasma membrane recruitment of DGKα are required for growth-factor-induced cell migration and ruffling, through the control of Rac small-GTPase activation and plasma membrane localization. Herein we unveil a signaling pathway through which DGKα coordinates the localization of Rac. We show that upon hepatocyte growth-factor stimulation, DGKα, by producing PA, provides a key signal to recruit atypical PKCζ/ι (aPKCζ/ι) in complex with RhoGDI and Rac at ruffling sites of colony-growing epithelial cells. Then, DGKα-dependent activation of aPKCζ/ι mediates the release of Rac from the inhibitory complex with RhoGDI, allowing its activation and leading to formation of membrane ruffles, which constitute essential requirements for cell migration. These findings highlight DGKα as the central element of a lipid signaling pathway linking tyrosine kinase growth-factor receptors to regulation of aPKCs and RhoGDI, and providing a positional signal regulating Rac association to the plasma membrane.cell migration | growth factors | phosphatidic acid C ell migration, central to many biological and pathological processes such as cancer metastatic progression, is a multistep cycle involving extension of protrusions and formation of stable attachments near the leading edge, followed by translocation of the cell body forward (1). The protrusive activity occurring at the leading edge depends on the spatial and temporal coordination between cell substrate adhesion and actin reorganization. Rhofamily small GTPases coordinate the recruitment at the leading edge of downstream effectors, thereby mediating the formation of ruffles and lamellipodia. Their GTP-bound state is tightly regulated by both guanine nucleotide exchange factors (GEFs), which stimulate GTP loading, and GTPase activating proteins (GAPs), which catalyze GTP hydrolysis. Moreover, Rho-family GTPases are regulated by guanine nucleotide dissociation inhibitors (GDIs), which antagonize both GEFs and GAPs and mediate the cycling of Rho proteins between the cytosol and the membrane (2, 3).Atypical protein kinase C ζ and ι (aPKCζ/ι), unlike classical and novel PKCs, feature a C1-like domain which does not bind to either diacylglycerol or phorbol esters, and have recently been proposed as key transducers for establishment of cell polarity and migration (4).Diacylglycerol kinases (DGKs), which convert diacylglycerol (DAG) to phosphatidic acid (PA), comprise a family of 10 distinct enzymes grouped into five classes, each featuring distinct regulatory domains and a highly conserved catalytic domain preceded by two cysteine-rich C1-like domains. An increasing body of evidence indicates that DGKs, by acting as terminators of diacylglyceroltriggered signaling, contribute to regulating C1 domain-containing proteins, such as classical and novel PKCs and the Rac-GAP β-chimaerin (5). ...

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Diacylglycerol Kinase ζ Regulates Actin Cytoskeleton Reorganization through Dissociation of Rac1 from RhoGDI

Cited by 73 publications

References 72 publications

Negative Charges in the Flexible N-Terminal Domain of Rho GDP-Dissociation Inhibitors (RhoGDIs) Regulate the Targeting of the RhoGDI–Rac1 Complex to Membranes

Negative Charges in the Flexible N-Terminal Domain of Rho GDP-Dissociation Inhibitors (RhoGDIs) Regulate the Targeting of the RhoGDI–Rac1 Complex to Membranes

Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis

Diacylglycerol kinase α mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI

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