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

2000 ◽  
Vol 118 (4) ◽  
pp. A179
Author(s):  
Terence T. Chiu ◽  
Enrique Rozengurt
Keyword(s):  
Protein Kinase ◽  
Pertussis Toxin ◽  
Lysophosphatidic Acid ◽  
Protein Kinase D

Lysophosphatidic acid rapidly induces protein kinase D activation through a pertussis toxin-sensitive pathway

2000 ◽  
Vol 278 (1) ◽  
pp. C33-C39 ◽  
Author(s):  
Lina Paolucci ◽  
James Sinnett-Smith ◽  
Enrique Rozengurt
Keyword(s):  
Protein Kinase ◽  
Pertussis Toxin ◽  
Lysophosphatidic Acid ◽  
Kinase Inhibitor ◽  
Structural Features ◽  
Protein Kinase D ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Swiss 3T3

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.

scholarly journals Cooperation of Gq, Gi, and G12/13in Protein Kinase D Activation and Phosphorylation Induced by Lysophosphatidic Acid

2002 ◽  
Vol 278 (7) ◽  
pp. 4882-4891 ◽  
Author(s):  
Jingzhen Yuan ◽  
Lee W. Slice ◽  
Jennifer Gu ◽  
Enrique Rozengurt
Keyword(s):  
Protein Kinase ◽  
Lysophosphatidic Acid ◽  
Protein Kinase D

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

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.

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

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.

scholarly journals Activation of the mitogen-activated protein kinase cascade by pertussis toxin-sensitive and -insensitive pathways in cultured ventricular cardiomyocytes

1995 ◽  
Vol 309 (2) ◽  
pp. 437-443 ◽  
Author(s):  
M A Bogoyevitch ◽  
A Clerk ◽  
P H Sugden
Keyword(s):  
Protein Kinase ◽  
Pertussis Toxin ◽  
Lysophosphatidic Acid ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Endothelin 1 ◽  
Ventricular Cardiomyocytes ◽  
Mitogen Activated Protein ◽  
Endothelin 3 ◽  
Two Peaks

The involvement of pertussis toxin (PTX)-sensitive and -insensitive pathways in the activation of the mitogen-activated protein kinase (MAPK) cascade was examined in ventricular cardiomyocytes cultured from neonatal rats. A number of agonists that activate heterotrimeric G-protein-coupled receptors stimulated MAPK activity after exposure for 5 min. These included foetal calf serum (FCS), endothelin-1 (these two being the most effective of the agonists examined), phenylephrine, endothelin-3, lysophosphatidic acid, carbachol, isoprenaline and angiotensin II. Activation of MAPK and MAPK kinase (MEK) by carbachol returned to control levels within 30-60 min, whereas activation by FCS was more sustained. FPLC on Mono Q showed that carbachol and FCS activated two peaks of MEK and two peaks of MAPK (p42MAPK and p44MAPK). Pretreatment of cells with PTX for 24 h inhibited the activation of MAPK by carbachol, FCS and lysophosphatidic acid, but not that by endothelin-1, phenylephrine or isoprenaline. Involvement of G-proteins in the activation of the cardiac MAPK cascade was demonstrated by the sustained (PTX-insensitive) activation of MAPK (and MEK) after exposure of cells to AlF4-. AlF4- activated PtdIns hydrolysis, as did endothelin-1, endothelin-3, phenylephrine and FCS. In contrast, the effect of lysophosphatidic acid on PtdIns hydrolysis was small and carbachol was without significant effect even after prolonged exposure. We conclude that PTX-sensitive (i.e. Gi/G(o)-linked) and PTX-insensitive (i.e. Gq/Gs-linked) pathways of MAPK activation exist in neonatal ventricular myocytes. FCS may stimulate the MAPK cascade through both pathways.

scholarly journals Regulation of lysophosphatidic acid-stimulated tyrosine phosphorylation of mitogen-activated protein kinase by protein kinase C- and pertussis toxin-dependent pathways in the endothelial cell line EAhy 926

1995 ◽  
Vol 307 (3) ◽  
pp. 743-748 ◽  
Author(s):  
A McLees ◽  
A Graham ◽  
K Malarkey ◽  
G W Gould ◽  
R Plevin
Keyword(s):  
Protein Kinase C ◽  
Endothelial Cell ◽  
Protein Kinase ◽  
Map Kinase ◽  
Cell Line ◽  
Tyrosine Phosphorylation ◽  
Pertussis Toxin ◽  
Lysophosphatidic Acid ◽  
Kinase C ◽  
Mitogen Activated Protein

In the endothelial cell line EAhy 926, 1-oleoyl-lysophosphatidic acid (LPA) stimulated the tyrosine phosphorylation of the pp42 isoform of mitogen-activated protein (MAP) kinase. Maximum phosphorylation was observed within 5 min of LPA addition, but the response was sustained for up to 120 min. Re-addition of LPA after 60 min stimulated a further sustained increase in the tyrosine phosphorylation of MAP kinase. In cells pretreated with phorbol 12-myristate 13-acetate (PMA; 24 h) or preincubated with the protein kinase C inhibitor Ro-318220, LPA-induced tyrosine phosphorylation of pp42 MAP kinase was substantially reduced at 2 min but potentiated at 60 min. Ro-318220 in combination with either PMA or pertussis toxin pretreatment abolished the LPA response at all time points, suggesting an involvement of protein kinase C in the pertussis toxin-sensitive part of the pathway. Agents which raised intracellular cyclic AMP levels did not affect the initial phase of LPA-stimulated MAP kinase activation, but abolished the late phase. However, this effect was prevented by Ro-318220, implicating a greater role for protein kinase C than protein kinase A in the regulation of sustained MAP kinase responses. LPA stimulated an increase in the tyrosine phosphorylation of focal adhesion kinase pp125 (pp125FAK) in EAhy 926 cells which was both protein kinase C- and pertussis toxin-independent. These results are discussed in terms of the pathways regulating both MAP kinase and pp125FAK in response to LPA in the EAhy 926 endothelial cells line.

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