Platelet‐activating factor (PAF) induces activation of matrix metalloproteinase 2 activity and vascular endothelial cell invasion and migration

Axelrad, T. William; Deo, Dayanand; Ottino, Paulo; Kirk, Jennefer Van; Bazán, Nicolás G.; Bazán, Haydee E. P.; Hunt, Jay D.

doi:10.1096/fj.03-0479fje

Cited by 47 publications

(42 citation statements)

References 58 publications

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“…8, K and I), confirming our recent data that MMP2 mRNA levels are not affected by PAF (55). However, as expected, after 8 h of PAF stimulation, an elevated level of active MMP2 was observed in the medium, which increased rapidly at 16 and 24 h of PAF exposure (Fig.…”

Section: Phosphorylation Of Fak and Its Binding To Various Proteins Isupporting

confidence: 90%

Activation of Platelet-activating Factor Receptor-coupled Gαq Leads to Stimulation of Src and Focal Adhesion Kinase via Two Separate Pathways in Human Umbilical Vein Endothelial Cells

Deo

Bazán

Hunt

2004

Journal of Biological Chemistry

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Platelet-activating factor (PAF), a phospholipid second messenger, has diverse physiological functions, including responses in differentiated endothelial cells to external stimuli. We used human umbilical vein endothelial cells (HUVECs) as a model system. We show that PAF activated pertussis toxin-insensitive G␣ q protein upon binding to its seven transmembrane receptor. Elevated cAMP levels were observed via activation of adenylate cyclase, which activated protein kinase A (PKA) and was attenuated by a PAF receptor antagonist, blocking downstream activity. Phosphorylation of Src by PAF required G␣ q protein and adenylate cyclase activation; there was an absolute requirement of PKA for PAFinduced Src phosphorylation. Immediate (1 min) PAFinduced STAT-3 phosphorylation required the activation of G␣ q protein, adenylate cyclase, and PKA, and was independent of these intermediates at delayed (30 min) and prolonged (60 min) PAF exposure. PAF activated PLC␤3 through its G␣ q protein-coupled receptor, whereas activation of phospholipase C␥1 (PLC␥1) by PAF was independent of G proteins but required the involvement of Src at prolonged PAF exposure (60 min). We demonstrate for the first time in vascular endothelial cells: (i) the involvement of signaling intermediates in the PAF-PAF receptor system in the induction of TIMP2 and MT1-MMP expression, resulting in the coordinated proteolytic activation of MMP2, and (ii) a receptor-mediated signal transduction cascade for the tyrosine phosphorylation of FAK by PAF. PAF exposure induced binding of p130 Cas , Src, SHC, and paxillin to FAK. Clearly, PAF-mediated signaling in differentiated endothelial cells is critical to endothelial cell functions, including cell migration and proteolytic activation of MMP2.

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Section: Phosphorylation Of Fak and Its Binding To Various Proteins Isupporting

confidence: 90%

Activation of Platelet-activating Factor Receptor-coupled Gαq Leads to Stimulation of Src and Focal Adhesion Kinase via Two Separate Pathways in Human Umbilical Vein Endothelial Cells

Deo

Bazán

Hunt

2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…Most recently, Axelrad et al (66) showed that PAF induced the transactivation of MT1-MMP and TIMP2 genes and the activation of MMP-2 in human umbilical vein endothelial cells. In these cells, MMP-2 activation occurred through a G␣ q protein-JAK-2-Src-mediated pathway (25,66). Negative regulation of MMPs by PAF has also been reported; Barletta et al (67) showed that 300 nM PAF down-regulated MT1-MMP and MMP-2 mRNA levels and reduced MMP-2 activation in isolated human neuroblastoma cell clones.…”

Section: Discussionmentioning

confidence: 99%

Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Melnikova

Mourad-Zeidan

Lev

et al. 2006

Journal of Biological Chemistry

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Overexpression of cAMP-response element (CRE)-binding protein (CREB) and activating transcription factor (ATF) 1 contributes to melanoma progression and metastasis at least in part by promoting tumor cell survival and stimulating matrix metalloproteinase (MMP) 2 expression. However, little is known about the regulation of CREB and ATF-1 activities and their phosphorylation within the tumor microenvironment. We analyzed the effect of platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, for its ability to activate CREB and ATF-1 in eight cultured human melanoma cell lines, and we found that PAF receptor (PAFR) was expressed in all eight lines. In metastatic melanoma cell lines, PAF induced CREB and ATF-1 phosphorylation via a PAFRmediated signal transduction mechanism that required pertussis toxin-insensitive G␣ q protein and adenylate cyclase activity and was antagonized by a cAMP-dependent protein kinase A and p38 MAPK inhibitors. Addition of PAF to metastatic A375SM cells stimulated CRE-dependent transcription, as observed in a luciferase reporter assay, without increasing the CRE DNA binding capacity of CREB. Furthermore, PAF stimulated the gelatinase activity of MMP-2 by activating transcription and MMP-2 expression. MMP-2 activation correlated with the PAF-induced increase in the expression of an MMP-2 activator, membrane type 1 MMP. PAF-induced expression of pro-MMP-2 was causally related to PAF-induced CREB and ATF-1 phosphorylation; it was prevented by PAFR antagonist and inhibitors of p38 MAPK and protein kinase A and was abrogated upon quenching of CREB and ATF-1 activities by forced overexpression of a dominant-negative form of CREB. PAFinduced MMP-2 activation was also down-regulated by p38 MAPK and protein kinase A inhibitors. Finally, PAFR antagonist PCA4248 inhibited the development of A375SM lung metastasis in nude mice. This result indicated that PAF acts as a promoter of melanoma metastasis in vivo. We proposed that metastatic melanoma cells overexpressing CREB/ATF-1 are better equipped than nonmetastatic cells to respond to PAF within the tumor microenvironment. cAMP-response element (CRE)2 -binding protein (CREB), activating transcription factor (ATF) 1, and CRE modulators are members of the large basic region leucine zipper superfamily of transcription factors that regulate gene expression in response to cAMP, intracellular Ca 2ϩ mobilization, and cell stimulation with growth factors (1). The ubiquitously expressed CREB and ATF-1 and the preferentially expressed (in neuroendocrine tissues) CRE modulator bind to complete and partial palindromic CRE DNA consensus sites 5Ј-TGACGTCA-3Ј and 5Ј-CGTCA-3Ј. These transcription factors induce genes involved in cellular metabolism and respiration, gene transcription, cell cycle regulation and cell survival, as well as growth factor and cytokine genes (reviewed in Ref. 1). The transcriptional activity of the DNA-bound CREB protein dimers is regulated by phosphorylation of the serine 133 site in the kinase-inducible domain, wh...

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“…The coordinate interaction of monocytes with activated platelets and collagen has been shown to induce the expression of MMP-9 (Galt et al, 2001). Likewise, proteolytic activity of endothelial cells is induced by their interaction with platelets (Axelrad et al, 2004). Therefore, as the role of MMPs in different biological systems is being revealed, there is a growing interest regard- ing the effect of platelets on protease production.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cδ Mediates Platelet-Induced Breast Cancer Cell Invasion

Alonso-Escolano

Medina

Cieslik

et al. 2006

J Pharmacol Exp Ther

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Platelets play an important role in carcinogenesis, but the underlying molecular mechanisms remain poorly understood. To investigate the effects of platelets on in vitro invasion of MCF7 human breast cancer cells, human MCF7 cells were used to study their interactions with platelets using aggregometry and cell invasion chambers. Zymography and quantitative polymerase chain reaction (PCR) were used to study matrix metalloproteinases (MMPs), whereas Western blot was used to study protein kinase C (PKC) ␦ in MCF7 cells. We observed that platelets promoted invasion of MCF7 cells (3-fold increase, p Ͻ 0.05, n ϭ 3) and that this process correlated with a dramatic increase in MMP-9 (8 fold-increase, p Ͻ 0.001, n ϭ 3), which is known to facilitate cancer cell invasion. Because both platelets and MCF7 cells have been shown to release MMP-9, we investigated the cellular source that accounted for this increase. The time course and the use of specific protein synthesis inhibitors demonstrated that most of the increase in MMP-9 levels derived from de novo synthesis of this protease by cancer cells.

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Platelet‐activating factor (PAF) induces activation of matrix metalloproteinase 2 activity and vascular endothelial cell invasion and migration

Cited by 47 publications

References 58 publications

Activation of Platelet-activating Factor Receptor-coupled Gαq Leads to Stimulation of Src and Focal Adhesion Kinase via Two Separate Pathways in Human Umbilical Vein Endothelial Cells

Activation of Platelet-activating Factor Receptor-coupled Gαq Leads to Stimulation of Src and Focal Adhesion Kinase via Two Separate Pathways in Human Umbilical Vein Endothelial Cells

Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Protein Kinase Cδ Mediates Platelet-Induced Breast Cancer Cell Invasion

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