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New Concepts in Phospholipase D Signaling in Inflammation and Cancer
Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA) and choline. PLD regulation in cells falls into two major signaling categories. One is via growth factors/mitogens, such as EGF, PDGF, insulin, and serum, and implicate...
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Formato: | Texto |
Lenguaje: | English |
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TheScientificWorldJOURNAL
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070604/ https://www.ncbi.nlm.nih.gov/pubmed/20623096 http://dx.doi.org/10.1100/tsw.2010.116 |
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author | Gomez-Cambronero, Julian |
author_facet | Gomez-Cambronero, Julian |
author_sort | Gomez-Cambronero, Julian |
collection | PubMed |
description | Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA) and choline. PLD regulation in cells falls into two major signaling categories. One is via growth factors/mitogens, such as EGF, PDGF, insulin, and serum, and implicates tyrosine kinases; the other is via the small GTPase proteins Arf and Rho. We summarize here our lab's and other groups' contributions to those pathways and introduce several novel concepts. For the mitogen-induced signaling, new data indicate that an increase in cell transformation in PLD2-overexpressing cells is due to an increase of de novo DNA synthesis induced by PLD2, with the specific tyrosine residues involved in those functions being Y and Y. Recent research has also implicated Grb2 in tyrosine phosphorylation of PLD2 that also involves Sos and the ERK pathway. The targets of phosphorylation within the PLD2 molecule that are key to its regulation have recently been precisely mapped. They are Y, Y, and Y and the responsible kinases are, respectively, EGFR, JAK3, and Src. Y is an inhibitory site and its phosphorylation explains the low PLD2 activity that exists in low-invasive MCF-7 breast cancer cells. Advances along the small GTPase front have implicated cell migration, as PLD1 and PLD2 cause an increase in chemotaxis of leukocytes and inflammation. PA is necessary for full chemotaxis. PA enriches the localization of the atypical guanine exchange factor (GEF), DOCK2, at the leading edge of polarized neutrophils. Further, extracellular PA serves as a neutrophil chemoattractant; PA enters the cell and activates the mTOR/S6K pathway (specifically, S6K). A clear connection between PLD with the mTOR/S6K pathway has been established, in that PA binds to mTOR and also binds to S6K independently of mTOR. Lastly, there is evidence in the upstream direction of cell signaling that mTOR and S6K keep PLD2 gene expression function down-regulated in basal conditions. In summary, the involvement of PLD2 in cell signaling continues to expand geometrically. It involves gene transcription, mitogenic and cell migration effects as seen in normal growth, tumor development, and inflammation. |
format | Text |
id | pubmed-3070604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | TheScientificWorldJOURNAL |
record_format | MEDLINE/PubMed |
spelling | pubmed-30706042011-04-04 New Concepts in Phospholipase D Signaling in Inflammation and Cancer Gomez-Cambronero, Julian ScientificWorldJournal Review Article Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA) and choline. PLD regulation in cells falls into two major signaling categories. One is via growth factors/mitogens, such as EGF, PDGF, insulin, and serum, and implicates tyrosine kinases; the other is via the small GTPase proteins Arf and Rho. We summarize here our lab's and other groups' contributions to those pathways and introduce several novel concepts. For the mitogen-induced signaling, new data indicate that an increase in cell transformation in PLD2-overexpressing cells is due to an increase of de novo DNA synthesis induced by PLD2, with the specific tyrosine residues involved in those functions being Y and Y. Recent research has also implicated Grb2 in tyrosine phosphorylation of PLD2 that also involves Sos and the ERK pathway. The targets of phosphorylation within the PLD2 molecule that are key to its regulation have recently been precisely mapped. They are Y, Y, and Y and the responsible kinases are, respectively, EGFR, JAK3, and Src. Y is an inhibitory site and its phosphorylation explains the low PLD2 activity that exists in low-invasive MCF-7 breast cancer cells. Advances along the small GTPase front have implicated cell migration, as PLD1 and PLD2 cause an increase in chemotaxis of leukocytes and inflammation. PA is necessary for full chemotaxis. PA enriches the localization of the atypical guanine exchange factor (GEF), DOCK2, at the leading edge of polarized neutrophils. Further, extracellular PA serves as a neutrophil chemoattractant; PA enters the cell and activates the mTOR/S6K pathway (specifically, S6K). A clear connection between PLD with the mTOR/S6K pathway has been established, in that PA binds to mTOR and also binds to S6K independently of mTOR. Lastly, there is evidence in the upstream direction of cell signaling that mTOR and S6K keep PLD2 gene expression function down-regulated in basal conditions. In summary, the involvement of PLD2 in cell signaling continues to expand geometrically. It involves gene transcription, mitogenic and cell migration effects as seen in normal growth, tumor development, and inflammation. TheScientificWorldJOURNAL 2010-07-07 /pmc/articles/PMC3070604/ /pubmed/20623096 http://dx.doi.org/10.1100/tsw.2010.116 Text en Copyright © 2010 Julian Gomez-Cambronero. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Article Gomez-Cambronero, Julian New Concepts in Phospholipase D Signaling in Inflammation and Cancer |
title | New Concepts in Phospholipase D Signaling in Inflammation and Cancer |
title_full | New Concepts in Phospholipase D Signaling in Inflammation and Cancer |
title_fullStr | New Concepts in Phospholipase D Signaling in Inflammation and Cancer |
title_full_unstemmed | New Concepts in Phospholipase D Signaling in Inflammation and Cancer |
title_short | New Concepts in Phospholipase D Signaling in Inflammation and Cancer |
title_sort | new concepts in phospholipase d signaling in inflammation and cancer |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070604/ https://www.ncbi.nlm.nih.gov/pubmed/20623096 http://dx.doi.org/10.1100/tsw.2010.116 |
work_keys_str_mv | AT gomezcambronerojulian newconceptsinphospholipasedsignalingininflammationandcancer |