ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways

Abstract

Vascular smooth muscle cells respond to the purinergic agonist ATP by increasing intracellular calcium concentration and increasing the rate of cell proliferation. In many cells the extracellular signal-regulated kinase (ERK) cascade plays an important role in cellular proliferation. We have studied the effect of extracellular ATP on ERK activation and cell proliferation. ATP binding to a UTP-sensitive P2Y nucleotide receptor activates ERK1/ERK2 in a time- and dose-dependent manner in coronary artery smooth muscle cells (CASMC). ATP-induced activation of ERK1/ERK2 is dependent on the dual-specificity kinase mitogen-activated protein kinase/ERK kinase (i.e., MEK) but independent of phosphatidylinositol 3-kinase (PI3K) activity. We provide evidence that both ERK1/ERK2 and PI3K activities are required for CASMC proliferation. Thus ATP-stimulation of CASMC proliferation requires independent activation of both the ERK and PI3K signaling pathways.

Extracellular adenosine triphosphate and adenosine in cancer

“…During skin wound healing, the release of extracellular ATP has been shown to be critical for efficient epithelial repair, revealing the role of purinergic signaling in general cell functions. Indeed, activation of ATP receptors stimulates the proliferation of epidermal keratinocytes (Greig et al, 2003) and smooth muscle cells (Wilden et al, 1998), and initiates migration of epithelial cells (Boucher et al, 2007). Likewise, extracellular ATP released from hepatocytes and Kupffer cells immediately after hepatectomy has been shown to promote liver regeneration (Gonzales et al, 2010).…”

Mitogen-activated signaling and cell cycle regulation in airway smooth muscle

“…Activation of ERK and PI 3-kinase has been shown to be required for vascular smooth muscle proliferation (122)(123)(124), and inhibition of proliferation by cAMP occurs via suppression of cyclin D 1 expression (125,126), as it does in airway smooth muscle (87). Finally, reactive oxygen species may be critical for vascular smooth muscle cell mitogenic signaling (127,128), as they are in airway myocytes (79).…”

Synthesis, characterization, and in vitro evaluation of the selective P2Y2 receptor antagonist AR-C118925

“…Furthermore, P2Y 2 receptor antagonists may be useful as novel cancer therapeutics, as the P2Y 2 receptor was shown to promote tumor metastasis via opening of the endothelial barrier [16]. Proliferation of different tumor and non-tumor cells [17][18][19][20][21], as well as the induction of cell cycle progression in vascular smooth muscle cells [22,23], was also attributed to P2Y 2 receptor activation. Another potential benefit for P2Y 2 receptor antagonists could be for patients suffering from nephrogenic diabetes insipidus acquired, for example, through chronic use of lithium in a bipolar disorder therapy.…”