The Na+/H+ exchanger NHE1 is required for directional migration stimulated via PDGFR-alpha in the primary cilium.
The Na+/H+ exchanger NHE1 is required for directional migration stimulated via PDGFR-alpha in the primary cilium.
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DOI：
10.1083/jcb.200806019
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发表时间：
2009-04-06
期刊：
影响因子：
--
通讯作者：
Pedersen SF
中科院分区：
文献类型：
--
作者：
Schneider L;Stock CM;Dieterich P;Jensen BH;Pedersen LB;Satir P;Schwab A;Christensen ST;Pedersen SF
我们以前证明，初级纤毛协调血小板衍生生长因子（PDGF）受体（PDGFR）α介导的生长停滞成纤维细胞迁移。在这项研究中，我们研究睫状体PDGFR-α和Na+/H+交换器NHE 1在定向细胞迁移中的功能关系。在NIH 3 T3细胞和小鼠胚胎成纤维细胞（MEFs）中，NHE 1信使RNA和蛋白水平在生长停滞期间上调，这伴随着纤毛形成。NHE 1上调在Tg 737 orpk MEFs中不受影响，其没有或非常短的初级纤毛。在生长停滞的NIH 3 T3细胞中，NHE 1被特异性PDGFR-α配体PDGF-AA激活。在生长停滞的NIH 3 T3细胞和野生型MEFs的伤口愈合试验中，5′-（N-乙基-N-异丙基）阿米洛利抑制NHE 1可有效降低PDGF-AA介导的定向迁移。这些影响强烈衰减间期NIH 3 T3细胞，这是缺乏初级纤毛，并在Tg 737 orpk MEFs。PDGF-AA未能刺激NHE 1-null成纤维细胞的迁移。总之，响应纤毛PDGFR-α信号的定向迁移刺激特异性依赖于NHE 1活性，表明NHE 1激活是PDGFR-α刺激生理反应中的关键事件。
We previously demonstrated that the primary cilium coordinates platelet-derived growth factor (PDGF) receptor (PDGFR) α–mediated migration in growth-arrested fibroblasts. In this study, we investigate the functional relationship between ciliary PDGFR-α and the Na+/H+ exchanger NHE1 in directional cell migration. NHE1 messenger RNA and protein levels are up-regulated in NIH3T3 cells and mouse embryonic fibroblasts (MEFs) during growth arrest, which is concomitant with cilium formation. NHE1 up-regulation is unaffected in Tg737orpk MEFs, which have no or very short primary cilia. In growth-arrested NIH3T3 cells, NHE1 is activated by the specific PDGFR-α ligand PDGF-AA. In wound-healing assays on growth-arrested NIH3T3 cells and wild-type MEFs, NHE1 inhibition by 5′-(N-ethyl-N-isopropyl) amiloride potently reduces PDGF-AA–mediated directional migration. These effects are strongly attenuated in interphase NIH3T3 cells, which are devoid of primary cilia, and in Tg737orpk MEFs. PDGF-AA failed to stimulate migration in NHE1-null fibroblasts. In conclusion, stimulation of directional migration in response to ciliary PDGFR-α signals is specifically dependent on NHE1 activity, indicating that NHE1 activation is a critical event in the physiological response to PDGFR-α stimulation.
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