Diacylglycerol, when simplicity becomes complex

Carrasco, Silvia; Mérida, Isabel

doi:10.1016/j.tibs.2006.11.004

Cited by 342 publications

(302 citation statements)

References 72 publications

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“…The influence of DG levels on subcellular distributions of signaling proteins (32, 33) is proposed to involve an increase in the affinity of specific proteins for membranes and/or downstream events caused by membrane recruitment of proteins with DG affinity (42). Our data do not reveal the mechanism by which EPATs are recruited to DG-rich membrane leaflets.…”

Section: Discussioncontrasting

confidence: 69%

Diacylglycerol Enrichment of Endoplasmic Reticulum or Lipid Droplets Recruits Perilipin 3/TIP47 during Lipid Storage and Mobilization

Skinner

Shew

Schwartz

et al. 2009

Journal of Biological Chemistry

135

140

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Fatty acid-induced triacylglycerol synthesis produces triacylglycerol droplets with a protein coat that includes perilipin 3/TIP47 and perilipin 4/S3-12. This study addresses the following two questions. Where do lipid droplets emerge, and how are their coat proteins recruited? We show that perilipin 3-and perilipin 4-coated lipid droplets emerge along the endoplasmic reticulum (ER Fat storage has become an area of great interest because as a population we are experiencing significant increases in adiposity and its associated metabolic complications. There is a direct correlation between levels of adiposity and fat accumulation outside adipocytes, which is associated with a vast array of pathologies. However, the mechanisms underlying cellular fat deposition are not well understood. One example of a metabolically important but poorly understood process is how fat gets into intracellular droplets and how the single membrane leaflet of amphipathic proteins and lipids assembles around these droplets. In previous work, we have demonstrated that when cells are given fatty acids they rapidly synthesize triacylglycerol (TG), 2 and a set of proteins moves from the cytosol to coat the nascent TG droplets (1-5). These fat coat proteins are members of the PAT family, and the name is an acronym derived from the first letter of the nonsystematic names of the original three family members, Perilipin/ADRP/TIP47 (6). Later, two other proteins, S3-12 and OXPAT, were added based on similar sequence and lipid binding behaviors (2, 4). We will use the newly described systematic nomenclature for the PAT proteins (7) as follows: perilipin 1 for perilipin; perilipin 2 for adipophilin/ADRP; perilipin 3 for PP17/TIP47; perilipin 4 for S3-12, and perilipin 5 for MLDP/LSDP5/OXPAT. Unlike some lipid droplet proteins, PAT proteins do not have an ER targeting signal and are not trafficked to lipid droplets through the secretory pathway (8 -10). PAT proteins have been described as either constitutively lipid-associated proteins (CPATs) or exchangeable lipid-binding proteins (EPATs) (5). Perilipin 1 and perilipin 2 are CPATs, because they are stabilized by lipid binding, and thus are almost always bound to lipid. Perilipin 3, perilipin 4, and perilipin 5 are EPATs, because they are stable when not bound to lipid, and thus can exchange between the cytosol and lipid droplet based on the metabolic state of the cells. For example, when the lipid surface is expanded by fatty acid-driven TG synthesis, perilipin 3, perilipin 4, and perilipin 5 move from cytosol to the lipid droplet membrane leaflet (5).The PAT proteins appear to play an important role in regulating intracellular lipid storage, and CPATs in particular appear to protect lipid stores from unregulated hydrolysis. Studies in cultured cells and whole animals show that CPAT

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Section: Discussioncontrasting

confidence: 69%

Diacylglycerol Enrichment of Endoplasmic Reticulum or Lipid Droplets Recruits Perilipin 3/TIP47 during Lipid Storage and Mobilization

Skinner

Shew

Schwartz

et al. 2009

Journal of Biological Chemistry

135

140

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“…It is generated by the hydrolysis of phosphatidylinositol 4,5-bisphosphate in response to the activation of surface receptors that include GPCRs and receptor tyrosine kinases [26]. In addition to its many cellular functions, DAG can also serve as a substrate for enzymes that generate alternative signalling lipids [27]. One pathway of particular interest invokes the DAGLs which hydrolyse DAG to form 2-AG-the most abundant ligand for CB1 and CB2 receptors.…”

Section: The Many Facets Of Endocannabinoidsmentioning

confidence: 99%

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

Skaper

Marzo²

2012

Phil. Trans. R. Soc. B

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The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related 'phytocannabinoid' compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the 'endocannabinoids' and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness.

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“…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). Conversely, by generating PA, DGKs regulate several signaling proteins, including serine kinases, small-GTPaseregulating proteins, and lipid-metabolizing enzymes (reviewed in refs.…”

mentioning

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, when simplicity becomes complex

Cited by 342 publications

References 72 publications

Diacylglycerol Enrichment of Endoplasmic Reticulum or Lipid Droplets Recruits Perilipin 3/TIP47 during Lipid Storage and Mobilization

Diacylglycerol Enrichment of Endoplasmic Reticulum or Lipid Droplets Recruits Perilipin 3/TIP47 during Lipid Storage and Mobilization

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

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

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