Lysophosphatidic Acid Interacts with Transforming Growth Factor-β Signaling to Mediate Keratinocyte Growth Arrest and Chemotaxis

Abstract

Lysophosphatidic acid (LPA, 1-acyl-glycerol-3-phosphate) plays an important role in diverse biological responses including cell proliferation, differentiation, survival, migration, and tumor cell invasion. The most prominent source of LPA is platelets from which it is released after thrombin activation and is assumed to be an essential function of this lysophospholipid in cutaneous wound closure. Therefore, we examined the role of LPA on biological responses of keratinocytes. Although LPA potently enhances keratinocyte migration, it strongly induces growth arrest of proliferating epidermal cells. Thus, LPA possesses analogous actions to transforming growth factor-beta (TGF-beta), which is also released from degranulating platelets at wounded sites. In contrast to LPA, the intracellular signaling events of TGF-beta have been clearly identified and indicate that Smad3 is involved in chemotaxis and cell growth arrest of keratinocytes induced by this cytokine. Here we show that LPA, although it does not alter TGF-beta release is capable to activate Smad3 and results in a heteromerization with Smad4 and binding of the complex to its specific DNA-promoter elements. LPA completely fails to induce chemotaxis in Smad3-deficient cells, whereas growth inhibition is at least in part reduced. These findings indicate an essential role of Smad3 in diverse biological properties of LPA-stimulated keratinocytes.

Reactive Oxygen Species Mediated Sustained Activation of Protein Kinase C α and Extracellular Signal-Regulated Kinase for Migration of Human Hepatoma Cell Hepg2

“…There might be some mechanistic link between cell cycle arrest and migration/invasion of tumor cells. For example, metastasis of tumor cell induced by cytokines such as transforming growth factor-h is often accompanied by growth inhibition (38,39). Interestingly, a lot of studies showed that PKC might crosstalk with or even mediate the effect of transforming growth factor-h signaling (40,41).…”

Production of Lysophosphatidic Acid in Blister Fluid: Involvement of a Lysophospholipase D Activity

“…Sauer et al (2004) showed that LPA mediates keratinocyte growth arrest and chemotaxis. The effects of LPA on wound healing have also been studied in intestinal epithelial cells (Liliom et al, 1998;Sturm et al, 1998;Hines et al, 2000), where LPA induced migration and proliferation.…”

Cross-talk between lysophosphatidic acid receptor 1 and tropomyosin receptor kinase A promotes lung epithelial cell migration

“…Ligand-receptor binding in the LPA/LPA1 signaling pathway promotes migration and enhances wound healing in vivo [7, 8]. In current study, we investigated the effect of TrkA on LPA-induced cell migration in lung epithelial cells and found that TrkA tyrosine kinase inhibitor or reduction of TrkA level significantly attenuated the LPA-induced cell migration.…”

“…LPA is a crucial mediator of physiological processes including cell proliferation, survival, migration, differentiation, adhesion and morphology, as well as pathological processes in cancer, fibrosis, bone metabolism and reproduction [3, 4]. In the setting of wound repair, LPA is released from serum by a platelet-dependent pathway [1] at the site of acute injury [5, 6], and then LPA promotes cell migration [7] and thus enhances wound healing [8]. …”