A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF
A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF
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DOI：
10.1152/ajpcell.00387.2013
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发表时间：
2014-06-01
影响因子：
5.5
通讯作者：
Choudhury, Goutam Ghosh
中科院分区：
文献类型：
--
作者：
Bera, Amit;Das, Falguni;Choudhury, Goutam Ghosh
血小板衍生生长因子BB及其受体(PDGFRβ)在肾小球系膜细胞的发育中起着关键作用。它们在系膜增生性肾小球肾炎时系膜细胞增殖增加中的作用早已被注意到，但调控这些变化的信号机制的操作逻辑仍不清楚。我们研究了最近发现的一种MAPK，ERK5，在这一过程中的作用。PDGF以时间依赖的方式增加ERK5的活化磷酸化和蛋白质的酪氨酸磷酸化。ERK5的药物抑制剂XMD8-92可阻断PDGF诱导的DNA合成和系膜细胞增殖。同样，显性阴性的ERK5或针对ERK5的siRNAs的表达阻断了PDGF刺激的DNA合成和增殖。抑制ERK5可减弱细胞周期蛋白D1mRNA和蛋白的表达，从而抑制CDK4介导的肿瘤抑制蛋白pRb的磷酸化。细胞周期蛋白D1或CDK4的表达可阻断显性阴性的ERK5或siErk5对PDGF诱导的系膜细胞DNA合成和增殖的抑制作用。我们先前已经证明，磷脂酰肌醇3-激酶(PI3-Kinase)在PDGF诱导的系膜细胞增殖中起作用。抑制PI3-激酶可阻断PDGF诱导的ERK5的磷酸化。由于PI3-K通过Akt发挥作用，我们确定了ERK5在Akt磷酸化中的作用。XMD8-92、显性负性ERK5和siErk5抑制PDGF对Akt的磷酸化。有趣的是，我们发现，在系膜细胞中，一种Akt激酶的药物抑制剂可以抑制PDGF诱导的ERK5的磷酸化。因此，我们的数据揭示了在PDGF诱导的系膜细胞增殖中，PI3-激酶结点下游ERK5和Akt之间存在正反馈微电路。
Platelet-derived growth factor BB and its receptor (PDGFR beta) play a pivotal role in the development of renal glomerular mesangial cells. Their roles in increased mesangial cell proliferation during mesangioproliferative glomerulonephritis have long been noted, but the operating logic of signaling mechanisms regulating these changes remains poorly understood. We examined the role of a recently identified MAPK, Erk5, in this process. PDGF increased the activating phosphorylation of Erk5 and tyrosine phosphorylation of proteins in a time-dependent manner. A pharmacologic inhibitor of Erk5, XMD8-92, abrogated PDGF-induced DNA synthesis and mesangial cell proliferation. Similarly, expression of dominant negative Erk5 or siRNAs against Erk5 blocked PDGF-stimulated DNA synthesis and proliferation. Inhibition of Erk5 attenuated expression of cyclin D1 mRNA and protein, resulting in suppression of CDK4-mediated phosphorylation of the tumor suppressor protein pRb. Expression of cyclin D1 or CDK4 prevented the dominant negative Erk5-or siErk5 mediated inhibition of DNA synthesis and mesangial cell proliferation induced by PDGF. We have previously shown that phosphatidylinositol 3-kinase (PI3-kinase) contributes to PDGF-induced proliferation of mesangial cells. Inhibition of PI3-kinase blocked PDGF-induced phosphorylation of Erk5. Since PI3-kinase acts through Akt, we determined the role of Erk5 on Akt phosphorylation. XMD8-92, dominant negative Erk5, and siErk5 inhibited phosphorylation of Akt by PDGF. Interestingly, we found inhibition of PDGF-induced Erk5 phosphorylation by a pharmacological inhibitor of Akt kinase and kinase dead Akt in mesangial cells. Thus our data unfold the presence of a positive feedback microcircuit between Erk5 and Akt downstream of PI3-kinase nodal point for PDGF-induced mesangial cell proliferation.