Cyclic stretch activates p38 SAPK2-, ErbB2-, and AT1-dependent signaling in bladder smooth muscle cells.
Cyclic stretch activates p38 SAPK2-, ErbB2-, and AT1-dependent signaling in bladder smooth muscle cells.
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DOI：
10.1152/ajpcell.2000.279.4.c1155
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发表时间：
2000-10
期刊：
影响因子：
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通讯作者：
Hiep T. Nguyen;R. Adam;S. Bride;John M. Park;Craig A. Peters;Michael R. Freeman
中科院分区：
文献类型：
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作者：
Hiep T. Nguyen;R. Adam;S. Bride;John M. Park;Craig A. Peters;Michael R. Freeman
膀胱平滑肌细胞(SMC)的周期性机械拉伸增加了DNA合成的速率，并刺激了肝素结合的表皮生长因子样生长因子(HB-EGF)基因的转录，HB-EGF是一种ErbB1/EGF受体配体，与肥厚性膀胱生长有关。在这项研究中，我们试图阐明负责拉伸刺激机械转导的信号通路。重复牵张可诱导原代培养大鼠膀胱SMC HB-EGF mRNA水平、DNA合成及AP-1/Ets DNA结合活性。P38SAPK2通路、血管紧张素受体1型(AT1)和ErbB2酪氨酸激酶的抑制剂降低了这些活性，而细胞外信号调节的丝裂原激活的蛋白激酶(Erk-MAPK)通路的抑制剂则没有作用。Stretch可快速激活应激激活蛋白激酶2(P38SAPK2)和Jun NH(2)末端激酶(JNK)/SAPK通路，但不能激活Erk-MAPK通路，并可诱导ErbB2磷酸化，但不能诱导ErbB1磷酸化。血管紧张素II(Ang II)是一种先前与拉伸反应相关的膀胱SMC有丝分裂原，但不激活ErbB2，而ErbB2的激活是在血管紧张素Ⅱ受体抑制剂存在的情况下发生的，这表明AT1介导的通路和ErbB2依赖的通路是通过独立的机制激活的。P38SAPK2和JNK/SAPK信号通路似乎也不依赖于ErbB2和AT1信号通路。这些发现表明，牵张刺激的正常膀胱SMC的DNA合成和基因表达是通过多个独立的受体系统(如AT1和ErbB2)和至少一个MAPK途径(P38SAPK2)来实现的。此外，我们还发现，ERK-MAPK通路在大多数系统中与依赖受体的细胞生长反应有关，但并不参与DNA合成的进程或HB-EGF基因对机械力的反应。
Cyclic mechanical stretch of bladder smooth muscle cells (SMC) increases rates of DNA synthesis and stimulates transcription of the gene for heparin-binding epidermal growth factor-like growth factor (HB-EGF), an ErbB1/EGF receptor ligand that has been linked to hypertrophic bladder growth. In this study we sought to clarify the signaling pathways responsible for mechanotransduction of the stretch stimulus. HB-EGF mRNA levels, DNA synthesis, and AP-1/Ets DNA binding activities were induced by repetitive stretch of primary culture rat bladder SMC. Inhibitors of the p38 SAPK2 pathway, the angiotensin receptor type 1 (AT1), and the ErbB2 tyrosine kinase reduced each of these activities, while an inhibitor of the extracellular signal-regulated kinase mitogen-activated protein kinase (Erk-MAPK) pathway had no effect. Stretch rapidly activated stress-activated protein kinase 2 (p38 SAPK2) and Jun NH(2)-terminal kinase (JNK)/SAPK pathways but not the Erk-MAPK pathway and induced ErbB2 but not ErbB1 phosphorylation. Angiotensin II (ANG II) a bladder SMC mitogen previously linked to the stretch response, did not activate ErbB2, and ErbB2 activation occurred in response to stretch in the presence of an ANG receptor inhibitor, indicating that activation of the AT1-mediated pathway and the ErbB2-dependent pathway occurs by independent mechanisms. p38 SAPK2 and JNK/SAPK signaling also appeared to be independent of the ErbB2 and AT1 pathways. These findings indicate that stretch-stimulated DNA synthesis and gene expression in normal bladder SMC occur via multiple independent receptor systems (e.g., AT1 and ErbB2) and at least one MAPK pathway (p38 SAPK2). Further, we show that the Erk-MAPK pathway, which in most systems is linked to receptor-dependent cell growth responses, is not involved in progression to DNA synthesis or in the response of the HB-EGF gene to mechanical forces.