Lysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype

Protein kinase D (PKD) is a serine-threonine protein kinase with distinct structural features and enzymological properties. Herein we demonstrate that lysophosphatidic acid (LPA) induces rapid PKD activation in mouse Swiss 3T3 and Rat-1 cells. LPA induced PKD activation in a concentration-dependent fashion with maximal stimulation (7.6-fold) achieved at 5 μM. Treatment of Swiss 3T3 cells with the protein kinase C (PKC) inhibitors GF-I, Ro-31–8220, and Gö-7874 completely abrogated PKD activation induced by LPA at concentrations that did not inhibit PKD activity when added directly to the in vitro kinase assays. PKD activation induced by LPA was attenuated markedly and selectively by prior exposure of either Swiss 3T3 or Rat-1 cells to pertussis toxin (PTx) in a concentration-dependent manner. In contrast, treatment with the protein tyrosine kinase inhibitor genistein, the MEK inhibitor PD-098059, or the phosphoinositide 3-kinase inhibitor wortmannin did not affect PKD activation in response to LPA. These results provide the first example of PTx-sensitive and PKC-dependent PKD activation and identify a novel Gi-dependent event in the action of LPA.

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Development of an arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic acid/protein kinase D signaling

Communications Biology ◽

10.1038/s42003-021-02308-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Yinan Jiang ◽

Yichen Guo ◽

Jinjin Hao ◽

Rachael Guenter ◽

Justin Lathia ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Protein Kinase ◽

Cancer Stem Cells ◽

Signaling Pathway ◽

Lysophosphatidic Acid ◽

Therapeutic Potential ◽

Protein Kinase D ◽

Breast Cancer Stem Cells ◽

Self Renewal

AbstractBreast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within the arteriolar niche in human estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs likely via differential regulation of CD36 transcription. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 -CD36 signaling pathway may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and effectively eliminating CSCs.

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Lysophosphatidic acid rapidly induces protein kinase D activation through a pertussis toxin-sensitive pathway in IEC-6 cells

Gastroenterology ◽

10.1016/s0016-5085(00)82793-6 ◽

2000 ◽

Vol 118 (4) ◽

pp. A179

Author(s):

Terence T. Chiu ◽

Enrique Rozengurt

Keyword(s):

Protein Kinase ◽

Pertussis Toxin ◽

Lysophosphatidic Acid ◽

Protein Kinase D

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Development of arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic Acid/protein kinase D signaling

10.21203/rs.3.rs-315714/v1 ◽

2021 ◽

Author(s):

Yinan Jiang ◽

Yichen Guo ◽

Jinjin Hao ◽

Rachael Guenter ◽

Justin Lathia ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Protein Kinase ◽

Cancer Stem Cells ◽

Signaling Pathway ◽

Lysophosphatidic Acid ◽

Therapeutic Potential ◽

Protein Kinase D ◽

Breast Cancer Stem Cells ◽

Self Renewal

Abstract Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within arteriolar niche in human estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 signaling pathway in combination with inhibition of CD36 function may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and eliminating CSCs.

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Activation of protein kinase C by lysophosphatidic acid: dependence on composition of phospholipid vesicles

Biochemical Journal ◽

10.1042/bj3170583 ◽

1996 ◽

Vol 317 (2) ◽

pp. 583-588 ◽

Cited By ~ 32

Author(s):

Julianne J. SANDO ◽

Olga I. CHERTIHIN

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Lysophosphatidic Acid ◽

Lipid Membrane ◽

Acyl Chain ◽

Lipid Vesicles ◽

Receptor Protein ◽

Lpa Receptor ◽

Kinase C ◽

Pkc Activation

Lysophosphatidic acid (LPA) has attracted recent attention as a major serum-derived regulator implicated in responses to vascular injury and inflammation, in tumour invasiveness and in neuronal signalling and remodelling. Although the possibility of a specific G-protein-coupled LPA receptor protein has been suggested, characterization of such a receptor is lacking. Since LPA can activate protein kinase C (PKC) pathways in many cells and PKC activators mimic many LPA effects, the possibility of more direct LPA effects on PKC was investigated. Phosphatidylcholine (PC)/phosphatidylserine (PS)/diacylglycerol (DAG) lipid vesicles of defined acyl chain composition were used to activate the enzyme. At total concentrations of saturated PC/PS+DAG vesicles (2–3 mM) that provided maximal PKC activation, 1–10 mol% [18:1]-LPA led to a further approx. 2-fold activation of PKCα. At lower lipid concentrations, a greater increase was observed with LPA concentrations up to 16–20 mol%. Higher concentrations of LPA were inhibitory. The LPA activation of PKC was dependent on the presence of DAG, PS and Ca2+. [18:1]-Lysophosphatidylcholine produced similar PKC activation in PC/PS/DAG vesicles. [14:0]-LPA was less effective, and longer-chain saturated lysolipids were ineffective. In unsaturated PC/PS vesicles, very little to no effect of LPA was discernable. These results suggest that physiologically or pathologically relevant concentrations of LPA can contribute to PKC activation depending on the composition of the lipid membrane. We hypothesize that LPA may affect the formation of lipid domains that are recognized by the enzyme.

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