Ras protein is involved in the physiological regulation of phospholipase D by platelet derived growth factor

Abstract

Lipid-derived metabolites play an important role in the regulation of cell responses to external stimuli, including cell growth control, transformation and apoptosis. Phospholipase D (PLD) is one of the critical elements in the regulation of lipid metabolism and the generation of second messengers, some of them involved in cell growth control. Oncogenic Ras proteins aect the activity of PLD by two alternate mechanisms, involving a positive activation and a feedback negative loop. Here we investigate the involvement of the proto-oncogenic Ras protein in the physiological activation of PLD induced by platelet-derived growth factor (PDGF). Overexpression of the wild type Ras protein or some of its regulatory components, such as Shc or Grb2, induces an ampli®cation of PLD activation by PDGF challenge. Furthermore, blocking the endogenous Ras by expression of the dominant negative mutant, H-Ras-Asn 17 completely eliminated the activation of PLD by PDGF. Thus, PDGF requires a complex system for PLD regulation implying the existence of at least two positive regulatory pathways, a Ras-dependent and a PKC-dependent mechanism. These results imply that PLD is an important element in signaling by Ras proteins that is altered after ras-induced transformation. Oncogene (2000) 19, 431 ± 437.

Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity

“…Although there is abundant information demonstrating activation of PLD by mitogenic stimulation of cells by growth factors, its involvement in the regulation of cell growth is not fully understood. Recently it has been demonstrated that Ras proteins are involved in the physiological regulation of PLD by PDGF (Lucas et al, 2000). On the other hand, PLD has been implicated in the acquisition of the transforming potential of murine ®broblasts (Lu et al, 2000) or the invasive capacity of transformed cells (Imamura et al, 1993) one of the most important determinants of malignant behavior (Herna ndez-Alcoceba et al, 2000).…”

Involvement of Phospholipase D in Sphingosine 1-Phosphate-induced Activation of Phosphatidylinositol 3-Kinase and Akt in Chinese Hamster Ovary Cells Overexpressing EDG3

“…For example, PLD and PI3K are regulated by receptor tyrosine kinases. Similar to PI3K, PLD is regulated by RalA, a downstream target of Ras, in plateletderived growth factor-and epidermal growth factor-stimulated cells (49,50), and PLD2 is tyrosine-phosphorylated by forming a physical complex with the epidermal growth factor receptor (51). Recent studies have demonstrated that PLD1 and PI3K play a role in GLUT4 translocation between the plasma membranes and intracellular vesicles in insulin-stimulated cells (52).…”

CO metabolism, sensing, and signaling

“…Remarkably, CO and exogenous compounds such as 3-(5 0 -hydroxymethyl-2 0 -furyl)-1-benzylindazole (YC-1) and 3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyradazolo [3,4-b]pyridine (BAY 41-2272) synergistically activate sGC to levels approximately similar to those induced by NO [88,89]. Such sGC induction leads to the increase of the cGMP level and to the activation of the cGMP-dependent protein kinase (PKG) phospho-transferase activity, thus affecting several cellular functions based on ion channel, phosphodiesterase, and protein kinase actions [77,80,[90][91][92][93][94][95].…”