Regulation of cell-cell interactions by phosphatidic acid phosphatase 2b/VCIP

Humtsoe, Joseph O.

doi:10.1093/emboj/cdg165

Cited by 65 publications

(127 citation statements)

References 60 publications

(76 reference statements)

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“…2E). LPP3 has recently been noted to contain an RGD sequence that interacts with ␤ 3 integrins and was therefore postulated to function in cell-cell interactions (26). Our results are consistent with an interaction between LPP3 and ␣ IIb ␤ 3 that may determine the lateral organization of LPP3 in the platelet membrane.…”

Section: C-e)supporting

confidence: 87%

“…Effects of LPP3 inactivation in mice are similar to those seen when wnt signaling is up-regulated and LPP3 inhibits wnt signaling in cultured cells (27). LPP3 has also been shown to serve as an integrin ligand that regulates cell-cell interactions through a unique RGD sequence in the second extracellular loop (26). Clearly, more subtle approaches are required to separate activity-dependent and independent functions of these proteins.…”

Section: Discussionmentioning

confidence: 82%

“…Newly synthesized chemical inhibitors identify LPP1 as a global regulator of LPA production and signaling in platelets. The dual function of LPP1 as a regulator of both LPA production and responsiveness may explain the complex and pleiotropic phenotypes associated with overexpression, misexpression, or down-regulation of this class of enzymes in many systems (19,21,(25)(26)(27)(28).…”

mentioning

confidence: 99%

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Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets

Smyth

Sciorra

Sigal

et al. 2003

Journal of Biological Chemistry

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Blood platelets play an essential role in ischemic heart disease and stroke contributing to acute thrombotic events by release of potent inflammatory agents within the vasculature. Lysophosphatidic acid (LPA) is a bioactive lipid mediator produced by platelets and found in the blood and atherosclerotic plaques. LPA receptors on platelets, leukocytes, endothelial cells, and smooth muscle cells regulate growth, differentiation, survival, motility, and contractile activity. Definition of the opposing pathways of synthesis and degradation that control extracellular LPA levels is critical to understanding how LPA bioactivity is regulated. We show that intact platelets and platelet membranes actively dephosphorylate LPA and identify the major enzyme responsible as lipid phosphate phosphatase 1 (LPP1). Localization of LPP1 to the platelet surface is increased by exposure to LPA. A novel receptor-inactive sn-3-substituted difluoromethylenephosphonate analog of phosphatidic acid that is a potent competitive inhibitor of LPP1 activity potentiates platelet aggregation and shape change responses to LPA and amplifies LPA production by agonist-stimulated platelets. Our results identify LPP1 as a pivotal regulator of LPA signaling in the cardiovascular system. These findings are consistent with genetic and cell biological evidence implicating LPPs as negative regulators of lysophospholipid signaling and suggest that the mechanisms involve both attenuation of lysophospholipid actions at cell surface receptors and opposition of lysophospholipid production.Lysophosphatidic acid (1-acylglycerol-3-phosphate, LPA) 1 is the prototypic member of a class of receptor-active lipid phosphoric acid mediators that function as intercellular signaling molecules. LPA and the structurally related compound sphingosine 1-phosphate (S1P) are present in biological fluids at physiologically relevant concentrations and exert many of their effects on target cells by binding to specific heterotrimeric GTP-binding protein (G-protein)-coupled cell surface receptors. Responses to stimulation with LPA and S1P include growth, differentiation, chemotaxis, smooth muscle contraction, and changes in cell morphology and motility through alterations in organization of the actin cytoskeleton (1-3).Blood plasma contains physiologically relevant levels of LPA (4). Because of the multiple actions of LPA on cells of the vasculature, a growing body of evidence suggests that LPA plays an important role in blood clotting, wound healing, and tissue regeneration (3). The mitogenic and chemotactic actions of LPA may also participate in the recruitment of monocytes and macrophages and aberrant stimulation of endothelial and vascular muscle cell growth that underlie intimal hyperplasia, formation of an atherosclerotic plaque, and progression of atherosclerosis (5). Elevated plasma levels of LPA have also been associated with ovarian and certain other gynecological cancers, where LPA may participate in autocrine or paracrine stimulation of tumor cell growth (6).LPA is a major ...

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Section: C-e)supporting

confidence: 87%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

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Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets

Smyth

Sciorra

Sigal

et al. 2003

Journal of Biological Chemistry

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“…VCIP is also known as a pro-angiogenic protein as addition of anti-VCIP antibody significantly blocked capillary morphogenesis of endothelial cells. 34,49,50 Because the efficiency of IRES-mediated translation is highly dependent on the cellular availability of IRES trans-acting factors, 44,51 and considering the important biological roles of VCIP, it is likely that the expression levels of VCIP's IRES trans-acting factors are consistently high in a broad range of cell types. Interestingly, VCIP IRES activity increases by 20-fold under hypoxic stress compared with normal cell culture conditions.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo comparison of viral and cellular internal ribosome entry sites for bicistronic vector expression

et al. 2011

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Bicistronic vectors are essential to achieve efficient expression of multiple genes in gene therapy protocols and biomedical applications. Internal ribosome entry site (IRES) elements have been utilized to initiate expression of an additional protein from a bicistronic vector. The IRES element commonly used in current bicistronic vectors originates from the encephalomyocarditis virus (EMCV). As IRES-mediated translation is dependent on availability of IRES trans-acting factors, which vary between cell types and species, adequate gene expression from the EMCV IRES element is not always achieved. To identify a novel IRES element that mediates gene expression consistently with a higher efficiency than the EMCV IRES, we tested 13 bicistronic reporter constructs containing different viral and cellular IRES elements. The in vitro screening in human and mouse fibroblast and hepatocarcinoma cells revealed that the vascular endothelial growth factor and type 1 collagen-inducible protein (VCIP) IRES was the only IRES element that directed translation more efficiently than the EMCV IRES in all cell lines. Furthermore, the VCIP IRES initiated greater reporter expression levels than the EMCV IRES in transfected mouse livers. These results suggest that VCIP-IRES containing vectors improve gene expression compared with those harboring an EMCV-IRES. This could increase the potential benefits of bicistronic vectors for experimental and therapeutic purposes.

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“…LPPs localized in the plasma membrane serve to attenuate the receptor-mediated signaling of extracellular LPA and S1P, which in turn activate a wide variety of signaling pathways such as PLC/ Ca ++ , Ras/ERK/MAPK, Rac, Rho and PI3K (Brindley, 2004, Moolenaar et al, 2004, Pyne et al, 2004. Furthermore, biological actions independent of their catalytic activity have been proposed for some LPPs (Escalante-Alcalde et al, 2003, Humtsoe et al, 2003, Zhao et al, 2005.…”

Section: Introductionmentioning

confidence: 99%

Generation of a reporter-null allele of Ppap2b/Lpp3and its expression during embryogenesis

Escalante‐Alcalde¹,

Morales²,

Stewart³

2009

Int. J. Dev. Biol.

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Our knowledge of how bioactive lipids participate during development has been limited principally due to the difficulties of working with lipids. The availability of some of these lipids is regulated by the Lipid phosphate phosphatases (LPPs). The targeted inactivation of Ppap2b, which codes for the isoenzyme Lpp3, has profound developmental defects. Lpp3 deficient embryos die around E9.5 due to extraembryonic vascular defects, making difficult to analyze its participation in later stages of mouse development. To gain some predictive information regarding the possible participation of Lpp3 in later stages of development, we generated a Ppap2b null reporter allele and it was used to establish its expression pattern in E8.5-13.5 embryos. We found that Ppap2b expression during these stages was highly dynamic with significant expression in structures where multiple inductive interactions occur such as the limb buds, mammary gland primordia, heart cushions and valves among others. These observations suggest that Lpp3 expression may play a key role in modulating/integrating multiple signaling pathways during development.

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Regulation of cell-cell interactions by phosphatidic acid phosphatase 2b/VCIP

Cited by 65 publications

References 60 publications

Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets

Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets

In vitro and in vivo comparison of viral and cellular internal ribosome entry sites for bicistronic vector expression

Generation of a reporter-null allele of Ppap2b/Lpp3and its expression during embryogenesis

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