JNK regulates serotonin-mediated proliferation and migration of pulmonary artery smooth muscle cells

Abstract

JNK is a member of the MAPK family and has essential roles in inflammation and cell differentiation and apoptosis. In recent years, there have been accumulating data indicating a novel role for JNK in cell growth and migration. In this report, we demonstrate that JNK activity is necessary for serotonin (5-HT)-induced proliferation and migration of bovine pulmonary artery smooth muscle cells (PASMCs). Stimulation with 5-HT was found to lead to activation of JNK with a maximal activation at 10 min. Inhibition of JNK with its specific inhibitor, SP-600125, or its dominant-negative form, DN-JNK, significantly reduced 5-HT-stimulated [(3)H]thymidine incorporation and cyclin D1 expression. A similar inhibitory effect on SMC migration produced by 5-HT, as detected by a wound healing assay, was observed with inhibition of JNK. Furthermore, inhibition of 5-HT receptors (1B) and (2A), but not inhibition of the 5-HT transporter, blocked 5-HT-induced JNK activation. Inhibition of phosphatidylinositol 3-kinase (PI3K) with LY-294002 and wortmannin had little or no effect on 5-HT-induced JNK phosphorylation, but JNK inhibitor SP-600125 and DN-JNK blocked 5-HT-stimulated phosphorylation of Akt and its downstream effectors, p70S6K1 and S6, indicating that Akt is a downstream effector of JNK. Activation of Akt by 5-HT was blocked only minimally, if at all, by inhibitors of ERK and p38 MAPK, indicating a uniqueness of JNK MAPK in this activation of Akt. Coimmunoprecipitation showed binding of Akt to JNK, further supporting the interaction of JNK and Akt. Thus JNK is a critical molecule in 5-HT-induced PASMC proliferation and migration and may act at an important point for cross talk of the MAPK and PI3K pathways. Its activation by 5-HT is initiated through 5-HT (1B) and (2A) receptors, and its stimulation of SMC proliferation and migration occurs through the Akt pathway.

Activation of JNK/c-Jun is required for the proliferation, survival, and angiogenesis induced by EET in pulmonary artery endothelial cells

“…Moreover, p21 CIP1 and p27 KIP1 , two important CDKIs, almost inhibit transition of the cell cycle at all stages. Therefore, their of JNK is a critical molecule in PASMC proliferation and tumor cell growth ( 32,33 ). In the present study, we observed that EETs promote the nuclear translocation of JNK and activate the JNK/c-Jun pathway, leading to the increase of PAEC growth and angiogenesis.…”

Mechanisms for PDGF, a Serum Cytokine, Stimulating Loss of Corneal Keratocyte Crystallins

“…Additionally, PDGF-induced TKT loss occurred in the presence of a PI3K, ERK and p38 inhibitor, but was not noted in the presence of a specific inhibitor of Akt that did not impact PI3K and of JNK that did not impact p38. These results indicate that PDGF induced loss of TKT via a signal pathway involving PI3K-independent Akt and JNK and are consistent with reports of a PI3K-independent Akt activation pathway [42] and of Akt crosstalk with JNK [43, 44]. …”

Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway

“…In addition, the p38MAPK and ERK regulated the cell cycle progression, which increased medial thickening and leads to vascular remodeling. Besides, time that the MAPK signaling pathways participate in the pathological process of hypoxiaPrevious reports have showed that 5-hydroxytryptamine (5-HT) stimulated PASMCs proliferation and migration by activating JNK [24]. However, our results identify that there were no changed in the expression of p-JNK in the pulmonary arterial from both PAH patients and rat PAH models.…”

“…JNK/stress activated protein kinase (SAPK) is response to growth factors, cytokines, environmental stress, ultraviolet light, oxidative stress, and heat shock [19][20][21][22][23]. It has been shown that activation of JNK by 5-hydroxytryptamine results in the enhanced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) [24]. Recent studies apoptosis as well as differentiation of s mesenchymal stem cells [25][26][27].…”