Proliferation versus migration in platelet-derived growth factor signaling -: The key role of endocytosis
Proliferation versus migration in platelet-derived growth factor signaling -: The key role of endocytosis
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DOI：
10.1074/jbc.m709428200
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发表时间：
2008-07-18
影响因子：
4.8
通讯作者：
Cirri, Paolo
中科院分区：
文献类型：
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作者：
De Donatis, Alina;Comito, Giusy;Cirri, Paolo
众所周知，血小板源性生长因子（PDGF）是间充质细胞迁移和增殖的关键调节因子。然而，这两种细胞反应是相互排斥的。为了解决这个明显的矛盾，我们研究了 NIH3T3 成纤维细胞对 PDGF 浓度增加的反应行为。我们发现，仅当 PDGF 浓度 > 5 ng/ml 时，才会产生强烈的细胞增殖诱导作用，而细胞迁移反应从 1 ng/ml 开始出现，并且在较高的 PDGF 浓度下可忽略不计。根据这些表型证据，我们的数据表明，细胞对 PDGF 的主要信号传导途径表现出不同的激活，作为刺激剂量的函数。在低 PDGF 浓度下，与细胞运动所需的细胞骨架重排相关的信号通路被最大程度地激活，而高 PDGF 浓度则激活与有丝分裂诱导相关的通路。我们的结果提出了一种机制，通过这种机制，细胞可以感知 PDGF 梯度的增加，从迁移表型转变为增殖表型。此外，我们提出细胞增殖或迁移的决定依赖于PDGF受体响应不同PDGF浓度的不同内吞途径。
It is common knowledge that platelet-derived growth factor (PDGF) is a critical regulator of mesenchymal cell migration and proliferation. Nevertheless, these two cellular responses are mutually exclusive. To solve this apparent contradiction, we studied the behavior of NIH3T3 fibroblasts in response to increasing concentrations of PDGF. We found that there is strong cell proliferation induction only with PDGF concentrations > 5 ng/ml, whereas the cell migration response arises starting from 1 ng/ml and is negligible at higher PDGF concentrations. According to these phenotypic evidences, our data indicate that cells display a differential activation of the main signaling pathways in response to PDGF as a function of the stimulation dose. At low PDGF concentrations, there is maximal activation of signaling pathways linked to cytoskeleton rearrangement needed for cell motility, whereas high PDGF concentrations activate pathways linked to mitogenesis induction. Our results suggest a mechanism by which cells switch from a migrating to a proliferating phenotype sensing the increasing gradient of PDGF. In addition, we propose that the cell decision to proliferate or migrate relies on different endocytotic routes of the PDGF receptor in response to different PDGF concentrations.