Phosphatidic Acid Induces Ligand-independent Epidermal Growth Factor Receptor Endocytic Traffic through PDE4 Activation

Norambuena, Andrés; Metz, Claudia; Jung, Juan E.; Silva, Antônia; Otero, Carolina; Cancino, Jorge; Retamal, Cláudio; Valenzuela, Juan Carlos Bustos; Soza, Andrea; González, Alfonso

doi:10.1091/mbc.e10-02-0167

Cited by 29 publications

(86 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This could suggest a possible suppressive or regulatory role for PLD2 in signalling. Previous work has shown involvement of PLD in membrane trafficking (Bi et al, 1997) and receptor internalisation (Antonescu et al, 2010;Norambuena et al, 2010). Upon pharmacological inhibition of both PLD1 and PLD2, or inhibition of PLD1 in PLD2KO neutrophils, we have shown an enhanced fMLP-induced ROS response (Fig.…”

Section: Discussionsupporting

confidence: 51%

PLD1 rather than PLD2 regulates phorbol-ester-, adhesion-dependent and Fcγ-receptor-stimulated ROS production in neutrophils

Norton

Zhang

Saqib

et al. 2011

Journal of Cell Science

View full text Add to dashboard Cite

SummaryThe signalling lipid phosphatidic acid (PA) is generated by the hydrolysis of phosphatidylcholine (PC), which is catalysed by phospholipase D (PLD) enzymes. Neutrophils, important cells of the innate immune system, maintain the body's defence against infection. Previous studies have implicated PLD-generated PA in neutrophil function; these have relied heavily on the use of primary alcohols to act as inhibitors of PA production. The recent development of isoform-selective small molecule inhibitors and the generation of a knockout mouse model provide us with accurate tools to study the role of PLDs in neutrophil responses. We show that PLD1 is a regulator of phorbol-ester-, chemoattractant, adhesion-dependent and Fc-receptor-stimulated production of reactive oxygen species (ROS) in neutrophils. Significantly we found that this role of PLD is isoform specific: the absence of PLD2 does not negatively affect these processes. Contrary to expectation, other functions required for an efficient immune response operate effectively in Pld2-deficient neutrophils or when both isoforms are inhibited pharmacologically. We conclude that although PLD1 does have important regulatory roles in neutrophils, the field has been confused by the use of primary alcohols; now that gold standard Pld-knockout mouse models are available, previous work might need to be reassessed.

show abstract

Section: Discussionsupporting

confidence: 51%

PLD1 rather than PLD2 regulates phorbol-ester-, adhesion-dependent and Fcγ-receptor-stimulated ROS production in neutrophils

Norton

Zhang

Saqib

et al. 2011

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Our data also suggest that this mechanism is relevant to human physiology, given the significant correlations between adipose tissue lipin 1 expression and lipolytic rates and PKA signaling in obese human subjects. Previous work on PA-mediated regulation of intracellular signaling events, including allosteric activation of mTOR (22) and PDE4 (20,25), linked the activity of PLD and DAG kinase enzymes to controlling this "signaling pool" of PA. An important finding of the present study is that the pool of PA dephosphorylated by lipin 1 that is likely destined for phosphoglycerolipid synthesis can regulate mTOR and PDE4 activity as well. It should be noted that PA was recently found to suppress formation of the mTORC2 complex (26); thus, further work is needed to determine whether mTORC1 is specifically activated by this pool of PA. We also acknowledge that we cannot rule out the possibility that alterations in other lipid species upstream or downstream of PA in these pathways are mediating these signaling events.…”

Section: Discussionmentioning

confidence: 99%

“…Previous work has linked PA accumulation to increased PDE4 activity in HeLa cells (20), but this "signaling" pool of PA has been thought to be regulated by the actions of phospholipase D (PLD) and other factors. In 3T3-L1 adipocytes, we found that knockdown of lipin 1 elicited a much greater increase in PDE activity than overexpression of PLD (Fig.…”

Section: Role For Pa In Controlling Cyclic Nucleotide Phosphodiesterasementioning

confidence: 99%

Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation

Mitra

Chen

Ren

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

101

View full text Add to dashboard Cite

Lipin 1 is a coregulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes a critical step in the synthesis of glycerophospholipids. Lipin 1 is highly expressed in adipocytes, and constitutive loss of lipin 1 blocks adipocyte differentiation; however, the effects of Lpin1 deficiency in differentiated adipocytes are unknown. Here we report that adipocyte-specific Lpin1 gene recombination unexpectedly resulted in expression of a truncated lipin 1 protein lacking PAP activity but retaining transcriptional regulatory function. Loss of lipin 1-mediated PAP activity in adipocytes led to reduced glyceride synthesis and increased PA content. Characterization of the deficient mice also revealed that lipin 1 normally modulates cAMP-dependent signaling through protein kinase A to control lipolysis by metabolizing PA, which is an allosteric activator of phosphodiesterase 4 and the molecular target of rapamycin. Consistent with these findings, lipin 1 expression was significantly related to adipose tissue lipolytic rates and protein kinase A signaling in adipose tissue of obese human subjects. Taken together, our findings identify lipin 1 as a reciprocal regulator of triglyceride synthesis and hydrolysis in adipocytes, and suggest that regulation of lipolysis by lipin 1 is mediated by PA-dependent modulation of phosphodiesterase 4.

show abstract

“…1B) (Zwang and Yarden 2006). In addition to p38 MAPK-regulated trafficking, internalization of ligand-free EGFR can be induced on activation of protein kinase C (PKC) or inhibition of protein kinase A (PKA) (Beguinot et al 1985;Lin et al 1986;Salazar and Gonzalez 2002;Norambuena et al 2010). In the case of VEGF, the activity of atypical PKC (aPKC) was shown to control vascular endothelial growth factor receptor (VEGFR) internalization and trafficking, thus regulating angiogenesis (Nakayama et al 2013).…”

Section: Stress Factors and Signaling Kinasesmentioning

confidence: 99%

Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

Miączyńska

2013

Cold Spring Harbor Perspectives in Biology

111

100

View full text Add to dashboard Cite

The intracellular trafficking machinery contributes to the spatial and temporal control of signaling by receptor tyrosine kinases (RTKs). The primary role in this process is played by endocytic trafficking, which regulates the localization of RTKs and their downstream effectors, as well as the duration and the extent of their activity. The key regulatory points along the endocytic pathway are internalization of RTKs from the plasma membrane, their sorting to degradation or recycling, and their residence in various endosomal compartments. Here I will review factors and mechanisms that modulate RTK signaling by (1) affecting receptor internalization, (2) regulating the balance between degradation and recycling of RTK, and (3) compartmentalization of signals in endosomes and other organelles. Cumulatively, these mechanisms illustrate a multilayered control of RTK signaling exerted by the trafficking machinery.

show abstract

Phosphatidic Acid Induces Ligand-independent Epidermal Growth Factor Receptor Endocytic Traffic through PDE4 Activation

Cited by 29 publications

References 81 publications

PLD1 rather than PLD2 regulates phorbol-ester-, adhesion-dependent and Fcγ-receptor-stimulated ROS production in neutrophils

PLD1 rather than PLD2 regulates phorbol-ester-, adhesion-dependent and Fcγ-receptor-stimulated ROS production in neutrophils

Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation

Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

Contact Info

Product

Resources

About