The phospholipase D superfamily as therapeutic targets

Frohman, Michael A.

doi:10.1016/j.tips.2015.01.001

Cited by 173 publications

(201 citation statements)

References 65 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…PLD2 (phospholipase D2) is one of two mammalian PLD enzymes that convert phosphatidylcholine to phosphatidic acid (PA) (79,80). PA stimulates membrane remodeling through several effector proteins, including phosphatidylinositol 4-phosphate 5 kinase (PI4P5K).…”

Section: Discussionmentioning

confidence: 99%

Role of Host Type IA Phosphoinositide 3-Kinase Pathway Components in Invasin-Mediated Internalization of Yersinia enterocolitica

et al. 2016

View full text Add to dashboard Cite

Many bacterial pathogens subvert mammalian type IA phosphoinositide 3-kinase (PI3K) in order to induce their internalization into host cells. How PI3K promotes internalization is not well understood. Also unclear is whether type IA PI3K affects different pathogens through similar or distinct mechanisms. Here, we performed an RNA interference (RNAi)-based screen to identify components of the type IA PI3K pathway involved in invasin-mediated entry of Yersinia enterocolitica, an enteropathogen that causes enteritis and lymphadenitis. The 69 genes targeted encode known upstream regulators or downstream effectors of PI3K. A similar RNAi screen was previously performed with the food-borne bacterium Listeria monocytogenes. The results of the screen with Y. enterocolitica indicate that at least nine members of the PI3K pathway are needed for invasin-mediated entry. Several of these proteins, including centaurin-␣1, Dock180, focal adhesion kinase (FAK), Grp1, LL5␣, LL5␤, and PLD2 (phospholipase D2), were recruited to sites of entry. In addition, centaurin-␣1, FAK, PLD2, and mTOR were required for remodeling of the actin cytoskeleton during entry. Six of the human proteins affecting invasin-dependent internalization also promote InlBmediated entry of L. monocytogenes. Our results identify several host proteins that mediate invasin-induced effects on the actin cytoskeleton and indicate that a subset of PI3K pathway components promote internalization of both Y. enterocolitica and L. monocytogenes. Many microbial pathogens exploit host signal transduction pathways in order to cause disease (1-4). One key pathway subverted by bacterial, viral, and protozoan pathogens involves a mammalian lipid kinase called type IA phosphoinositide 3-kinase (PI3K) (3). Type IA PI3K plays a critical role in internalization of several pathogens into host cells. These microbes include bacteria that cause anthrax (Bacillus anthracis) (5), respiratory infections (Pseudomonas aeruginosa and Chlamydia pneumoniae) (6, 7), and food-borne disease (Campylobacter jejuni and Listeria monocytogenes) (3,4,8). Type IA PI3K also promotes entry of Ebola virus (9), influenza A virus (10), and parasites causing Chagas' disease (Trypanosoma cruzi) (11) or toxoplasmosis (Toxoplasma gondii) (12). Overall, the mechanism by which this mammalian lipid kinase controls infection by these diverse pathogens is not well understood.Mammalian type IA PI3K is an heterodimeric enzyme composed of a 110-kDa catalytic subunit and a 85-kDa regulatory subunit (13). This PI3K is coupled to growth factor, cytokine, or cell adhesion receptors and controls a variety of processes, including cell growth, survival, and motility (13,14). Type IA PI3K promotes its biological effects through at least two mechanisms, the best understood of which involves lipid kinase activity. This PI3K produces phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], a lipid second messenger. PI(3,4,5)P 3 is converted by phosphatases to phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ]. Together, PI(3,4,5...

show abstract

Section: Discussionmentioning

confidence: 99%

Role of Host Type IA Phosphoinositide 3-Kinase Pathway Components in Invasin-Mediated Internalization of Yersinia enterocolitica

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Roles for PLD2 in thrombotic disease ( 37,66 ), cancer ( 67, 68 ), Alzheimer's disease (AD) ( 69 ), and immune function ( 65 ), based on animal model studies, have recently been summarized ( 5 ). Other potential functions have been raised by tissue culture studies, some of which will be reviewed here.…”

Section: Pld2mentioning

confidence: 99%

“…However, because of a 1,000-fold higher preference for primary alcohols ( 2 ), production of phosphatidylalcohol ( 4 ) is the primary outcome when even relatively modest amounts (1-3%) of ethanol or 1-butanol are present ( 5 ). Phosphatidylethanol (PtdEtOH) has a long half-life relative to ethanol and can be detected in serum for up to a month subsequent to alcohol consumption ( 6 ), making it an increasingly popular biomarker for assessment of acute and even chronic drinking.…”

mentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

Nelson

Frohman

2015

Journal of Lipid Research

Self Cite

110

View full text Add to dashboard Cite

“…PLD was cloned in the mid-1990s and two isoforms of PLD, PLD1 and PLD2 have been sequenced, extensively characterized and shown to possess phospholipase activity ((Hammond et al 1995, Colley et al 1997) and reviewed in (Frohman & Morris 1996, Frohman 2015). Both of these isoenzymes utilize phosphatidylcholine as a substrate and require PIP 2 as a cofactor.…”

Section: Phospholipase Dmentioning

confidence: 99%

“…Lopez et al 1998), and apparently also by cytoskeletal elements, as well as the supply of PIP2 (reviewed in Selvy et al 2011). Both PLDs are likely to play a role in vesicle trafficking within the cell, as well as in cellular responses to hormones and other receptor ligands (reviewed in Frohman & Morris 1996, Peng and Frohman 2012, Frohman 2015. Four other PLD isoforms, PLD3-6, have also been identified in the genome based on homology, but these have been much less studied, and in many cases whether or not the gene products actually exhibit PLD activity is not known.…”

Section: Phospholipase Dmentioning

confidence: 99%

Role of phospholipases in adrenal steroidogenesis

Bollag¹

2016

Journal of Endocrinology

View full text Add to dashboard Cite

Phospholipases are lipid-metabolizing enzymes that hydrolyze phospholipids. In some cases, their activity results in remodeling of lipids and/or allows the synthesis of other lipids. In other cases, however, and of interest to the topic of adrenal steroidogenesis, phospholipases produce second messengers that modify the function of a cell. In this review, the enzymatic reactions, products, and effectors of three phospholipases, phospholipase C, phospholipase D, and phospholipase A 2 , are discussed. Although much data have been obtained concerning the role of phospholipases C and D in regulating adrenal steroid hormone production, there are still many gaps in our knowledge. Furthermore, little is known about the involvement of phospholipase A 2 , perhaps, in part, because this enzyme comprises a large family of related enzymes that are differentially regulated and with different functions. This review presents the evidence supporting the role of each of these phospholipases in steroidogenesis in the adrenal cortex.

show abstract

The phospholipase D superfamily as therapeutic targets

Cited by 173 publications

References 65 publications

Role of Host Type IA Phosphoinositide 3-Kinase Pathway Components in Invasin-Mediated Internalization of Yersinia enterocolitica

Role of Host Type IA Phosphoinositide 3-Kinase Pathway Components in Invasin-Mediated Internalization of Yersinia enterocolitica

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

Role of phospholipases in adrenal steroidogenesis

Contact Info

Product

Resources

About