Gq-coupled purinergic receptors inhibit insulin-like growth factor-I/phosphoinositide 3-kinase pathway-dependent keratinocyte migration.
Gq-coupled purinergic receptors inhibit insulin-like growth factor-I/phosphoinositide 3-kinase pathway-dependent keratinocyte migration.
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DOI：
10.1091/mbc.e09-06-0497
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发表时间：
2010-03-15
影响因子：
3.3
通讯作者：
Lehmann M
中科院分区：
文献类型：
--
作者：
Taboubi S;Garrouste F;Parat F;Pommier G;Faure E;Monferran S;Kovacic H;Lehmann M
皮肤伤口后，释放的生长因子和细胞外核苷酸调节愈合的不同阶段，包括上皮再形成。在这里，我们发现，在角质形成细胞中，嘌呤能 P2Y2 受体抑制运动性 IGF-I/PI3K 通路。因此，细胞外核苷酸可能在伤口后皮肤重塑过程中发挥关键作用。磷酸肌醇 3 激酶 (PI3K) 的胰岛素样生长因子-I (IGF-I) 激活是表皮伤口愈合所需的角质形成细胞迁移的重要途径。我们之前报道过，细胞外核苷酸激活 Gα(q/11) 偶联的 P2Y2 嘌呤能受体会延迟角质形成细胞伤口的闭合。在这里，我们报告细胞外 UTP 激活 P2Y2 受体会抑制 IGF-I 诱导的 p110α-PI3K 激活。使用 siRNA 和药理学抑制剂，我们证明 UTP 对 PI3K 通路的拮抗作用是由 Gα(q/11)（而不是 G(i/o））介导的，与磷脂酶 Cβ 无关。嘌呤能信号传导不会影响 IGF-I 受体/胰岛素受体底物-I/p85 复合物的形成，但会阻断膜靶向活性 p110α 突变体的活性，表明 UTP 在 PI3K 膜募集的下游发挥作用。研究还发现，UTP 可以在几分钟内有效减弱 IGF-I 诱导的 PI3K 控制的肌动蛋白成核蛋白 cortactin 向质膜的易位。这支持UTP改变后来的迁徙事件的能力。事实上，UTP 以 Gα(q/11) 依赖性方式抑制 IGF-I 或膜靶向活性 p110α 突变体促进的角质形成细胞扩散和迁移。这些发现为受体酪氨酸激酶和 Gα(q/11) 偶联受体之间的信号串扰提供了新的见解，这种信号串扰对 p110α-PI3K 活性和角质形成细胞迁移产生相反的影响。
After skin wound, released growth factors and extracellular nucleotides regulate the different phases of healing, including re-epithelialization. Here, we show that, in keratinocytes, purinergic P2Y2 receptors inhibit the motogenic IGF-I/PI3K pathway. Therefore, extracellular nucleotides may play key roles during skin remodelling after wound. Insulin-like growth factor-I (IGF-I) activation of phosphoinositol 3-kinase (PI3K) is an essential pathway for keratinocyte migration that is required for epidermis wound healing. We have previously reported that activation of Gα(q/11)-coupled-P2Y2 purinergic receptors by extracellular nucleotides delays keratinocyte wound closure. Here, we report that activation of P2Y2 receptors by extracellular UTP inhibits the IGF-I–induced p110α-PI3K activation. Using siRNA and pharmacological inhibitors, we demonstrate that the UTP antagonistic effects on PI3K pathway are mediated by Gα(q/11)—and not G(i/o)—independently of phospholipase Cβ. Purinergic signaling does not affect the formation of the IGF-I receptor/insulin receptor substrate-I/p85 complex, but blocks the activity of a membrane-targeted active p110α mutant, indicating that UTP acts downstream of PI3K membrane recruitment. UTP was also found to efficiently attenuate, within few minutes, the IGF-I–induced PI3K-controlled translocation of the actin-nucleating protein cortactin to the plasma membrane. This supports the UTP ability to alter later migratory events. Indeed, UTP inhibits keratinocyte spreading and migration promoted by either IGF-I or a membrane-targeted active p110α mutant, in a Gα(q/11)-dependent manner both. These findings provide new insight into the signaling cross-talk between receptor tyrosine kinase and Gα(q/11)-coupled receptors, which mediate opposite effects on p110α-PI3K activity and keratinocyte migration.
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影响因子：
4.8
作者：
Bommakanti, RK;Vinayak, S;Simonds, WF
通讯作者：
Simonds, WF
影响因子：
3.4
作者：
Golebiewska, Urszula;Scarlata, Suzanne
通讯作者：
Scarlata, Suzanne
DOI：
10.1083/jcb.153.3.491
发表时间：
2001-04-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Erb L;Liu J;Ockerhausen J;Kong Q;Garrad RC;Griffin K;Neal C;Krugh B;Santiago-Pérez LI;González FA;Gresham HD;Turner JT;Weisman GA
通讯作者：
Weisman GA
影响因子：
4.1
作者：
Balciunaite, E;Kazlauskas, A
通讯作者：
Kazlauskas, A
影响因子：
4.1
作者：
Ballou, LM;Chattopadhyay, M;Lin, RZ
通讯作者：
Lin, RZ