Diacylglycerol kinase ζ regulates RhoA activation via a kinase-independent scaffolding mechanism

Ard, Ryan; Mulatz, Kirk; Abramovici, Hanan; Maillet, Jean-Christian; Fottinger, Alexandra; Foley, Tanya; Byham, Michèle-Renée; Iqbal, Tasfia Ahmed; Yoneda, Atsuko; Couchman, John R.; Parks, Robin J.; Gee, Stephen H.

doi:10.1091/mbc.e12-01-0026

Cited by 17 publications

(48 citation statements)

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“…The significance of these findings relates to our previous work, which established DGKζ as a critical regulator of both Rac1 and RhoA activity [28,29]. In the former case, we showed DGKζ-derived PA activates PAK1, which phosphorylates RhoGDI, allowing for the release and subsequent Rac1 activation.…”

Section: Discussionsupporting

confidence: 81%

Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion

et al. 2014

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BackgroundUnraveling the signaling pathways responsible for the establishment of a metastatic phenotype in carcinoma cells is critically important for understanding the pathology of cancer. The acquisition of cell motility is a key property of metastatic tumor cells and is a prerequisite for invasion. Rho GTPases regulate actin cytoskeleton reorganization and the cellular responses required for cell motility and invasion. Diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates diacylglycerol to yield phosphatidic acid, regulates the activity of the Rho GTPases Rac1 and RhoA. DGKζ mRNA is highly expressed in several different colon cancer cell lines, as well as in colon cancer tissue relative to normal colonic epithelium, and thus may contribute to the metastatic process.MethodsTo investigate potential roles of DGKζ in cancer metastasis, a cellular, isogenic model of human colorectal cancer metastatic transition was used. DGKζ protein levels, Rac1 and RhoA activity, and PAK phosphorylation were measured in the non-metastatic SW480 adenocarcinoma cell line and its highly metastatic variant, the SW620 line. The effect of DGKζ silencing on Rho GTPase activity and invasion through Matrigel-coated Transwell inserts was studied in SW620 cells. Invasiveness was also measured in PC-3 prostate cancer and MDA-MB-231 breast cancer cells depleted of DGKζ.ResultsDGKζ protein levels were elevated approximately 3-fold in SW620 cells compared to SW480 cells. There was a concomitant increase in active Rac1 in SW620 cells, as well as substantial increases in the expression and phosphorylation of the Rac1 effector PAK1. Similarly, RhoA activity and expression were increased in SW620 cells. Knockdown of DGKζ expression in SW620 cells by shRNA-mediated silencing significantly reduced Rac1 and RhoA activity and attenuated the invasiveness of SW620 cells in vitro. DGKζ silencing in highly metastatic MDA-MB-231 breast cancer cells and PC-3 prostate cancer cells also significantly attenuated their invasiveness.ConclusionElevated DGKζ expression contributes to increased Rho GTPase activation and the enhanced motility of metastatic cancer cells. These findings warrant further investigation of the clinical relevance of DGKζ upregulation in colon and other cancers. Interfering with DGKζ function could provide a means of inhibiting invasion and metastasis.

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Section: Discussionsupporting

confidence: 81%

Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion

et al. 2014

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“…For example, DAG recruits DAG kinase ζ, which phosphorylates DAG to generate PA and functions as a protein scaffold to activate RhoA, which orchestrates reorganization of the actin cytoskeleton in many settings [65, 66]. Altogether, DAG’s function in fission of mitochondria may be to drive actin filament polymerization at sites of ER constriction in collaboration with Myosin II and INF2, thereby permitting the ER to squeeze the future sites of fission to a diameter that Drp1 activity can then proceed with.…”

Section: Roles For Diacylglycerol In Fission Of Mitochondriamentioning

confidence: 99%

Role of mitochondrial lipids in guiding fission and fusion

Frohman

2014

J Mol Med

105

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Clinically-important links have been established between mitochondrial function and cardiac physiology and disease in the context of signaling mechanisms, energy production, and muscle cell development. The proteins and processes that drive mitochondrial fusion and fission are now known to have emergent functions in intracellular calcium homeostasis, apoptosis, vascular smooth muscle cell proliferation, myofibril organization, and Notch-driven cell differentiation, all key issues in cardiac disease. Moreover, decreasing fission may confer protection against ischemic heart disease, particularly in the setting of obesity, diabetes, and heart failure. The importance of lipids in controlling mitochondrial fission and fusion is increasing becoming appreciated. Roles for the bulk and signaling lipids cardiolipin, phosphatidylethanolamine, phosphatidic acid, diacylglycerol, and lysophosphatidic acid and the enzymes that synthesize or metabolize them in the control of mitochondrial shape and function are reviewed here. A number of diseases have been linked to loss-of-function alleles for a subset of the enzymes, emphasizing the importance of the lipid environment in this context.

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“…Thus, close parallelism exists between the DGKα driven aPKC recruitment in epithelial cells and the DGKζ mediated recruitment of PAK1 in MEFs, both controlling Rac1 activity and migration. Moreover, DGKζ also regulates RhoA activity in MEFs by acting as a scaffolding protein independently of PA production (Ard et al, 2012). DGKζ is also highly expressed in colon cancer cell lines and its expression correlates with enhanced cell motility due to increased Rac1 and RhoA activation (Cai et al, 2014), suggesting that DGKζ is a key regulator of Rho GTPase activity and cell migration in fibroblasts and tumor cells (Figure 2B).…”

Section: Dgks In Directional Migrationmentioning

confidence: 99%

Diacylglycerol Kinases: Shaping Diacylglycerol and Phosphatidic Acid Gradients to Control Cell Polarity

Baldanzi

Bettio

Malacarne

et al. 2016

Front. Cell Dev. Biol.

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Diacylglycerol kinases (DGKs) terminate diacylglycerol (DAG) signaling and promote phosphatidic acid (PA) production. Isoform specific regulation of DGKs activity and localization allows DGKs to shape the DAG and PA gradients. The capacity of DGKs to constrain the areas of DAG signaling is exemplified by their role in defining the contact interface between T cells and antigen presenting cells: the immune synapse. Upon T cell receptor engagement, both DGK α and ζ metabolize DAG at the immune synapse thus constraining DAG signaling. Interestingly, their activity and localization are not fully redundant because DGKζ activity metabolizes the bulk of DAG in the cell, whereas DGKα limits the DAG signaling area localizing specifically at the periphery of the immune synapse. When DGKs terminate DAG signaling, the local PA production defines a new signaling domain, where PA recruits and activates a second wave of effector proteins. The best-characterized example is the role of DGKs in protrusion elongation and cell migration. Indeed, upon growth factor stimulation, several DGK isoforms, such as α, ζ, and γ, are recruited and activated at the plasma membrane. Here, local PA production controls cell migration by finely modulating cytoskeletal remodeling and integrin recycling. Interestingly, DGK-produced PA also controls the localization and activity of key players in cell polarity such as aPKC, Par3, and integrin β1. Thus, T cell polarization and directional migration may be just two instances of the general contribution of DGKs to the definition of cell polarity by local specification of membrane identity signaling.

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Diacylglycerol kinase ζ regulates RhoA activation via a kinase-independent scaffolding mechanism

Cited by 17 publications

References 50 publications

Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion

Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion

Role of mitochondrial lipids in guiding fission and fusion

Diacylglycerol Kinases: Shaping Diacylglycerol and Phosphatidic Acid Gradients to Control Cell Polarity

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