Receptor tyrosine kinases modulate distinct transcriptional programs by differential usage of intracellular pathways.
Receptor tyrosine kinases modulate distinct transcriptional programs by differential usage of intracellular pathways.
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DOI：
10.7554/elife.07186
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发表时间：
2015-05-07
期刊：
影响因子：
7.7
通讯作者：
Soriano P
中科院分区：
文献类型：
--
作者：
Vasudevan HN;Mazot P;He F;Soriano P
受体酪氨酸激酶(RTK)通过共享的细胞内通路传递信号，但在许多细胞类型中调节不同的结果。为了探讨RTK在颅面发育中的特异性机制，我们用RNA-seq技术研究了小鼠胚胎腭间充质细胞对血小板衍生生长因子(PDGF)和成纤维细胞生长因子(FGF)信号的转录反应。虽然这两种生长因子诱导的早期基因表达谱在性质上是相似的，但晚期的反应是不同的。比较MEK(丝裂原/细胞外信号调节激酶)和PI3K(磷脂酰肌醇-3-激酶)的抑制作用，我们发现成纤维细胞生长因子的反应是MEK依赖的，而PDGF的反应是PI3K依赖的。此外，成纤维细胞生长因子促进增殖，而血小板衍生生长因子促进分化。最后，我们证明了PDGF-PI3K信号通路的重叠区域和腭部成骨细胞的分化，并在成纤维细胞生长因子突变体中增加了成骨，表明这种分化回路在体内是保守的。我们的结果确定了对PDGF和成纤维细胞生长因子的不同反应，并提供了对RTK特异性编码机制的洞察。DOI：http://dx.doi.org/10.7554/eLife.07186.001细胞产生许多不同的蛋白质，扮演着各种重要的角色。例如，被称为受体酪氨酸激酶的蛋白质可以检测特定的分子并向细胞的其他部分发送信号，以调节参与细胞分裂、运动和其他过程的基因的活动(或“表达”)。人类有58个受体酪氨酸激酶，这些蛋白的缺陷与癌症和糖尿病等疾病有关。然而，许多不同的受体调节共享的基因集的活动，因此尚不清楚单个受体如何具体控制特定过程中涉及的基因。两种受体酪氨酸激酶，称为PDGFR和FGFR，对人类和其他动物的面部、腭部和头部的发育至关重要。Vasudevan等人。使用了一种名为RNA测序的技术来找出小鼠上颌骨细胞中哪些基因受这些受体的调控。实验表明，有一组常见的基因，它们的活性在1小时内迅速变化，以响应PDGFR或FGFR的激活。然而，几个小时后，PDGFR被激活的细胞与FGFR活跃的细胞相比，具有不同的基因表达模式。Vasudevan等人。研究还发现，FGFR促进细胞分裂，而PDGFR促进腭部细胞分化为不同类型的细胞，具有更特殊的作用。这些不同的结果是因为PDGFR和FGFR使用不同的信号通路，涉及不同的蛋白质。例如，一种名为PI3K的蛋白质对PDGFR引起的基因表达变化至关重要，但对FGFR不起作用。这些结果表明，PGDRF和FGFR通过向细胞内发送不同的信号来控制腭部不同的细胞过程。了解受体酪氨酸激酶及其激活的基因网络将有助于我们识别对其他过程重要的信号，例如面部的发育。DOI：http://dx.doi.org/10.7554/eLife.07186.002
Receptor tyrosine kinases (RTKs) signal through shared intracellular pathways yet mediate distinct outcomes across many cell types. To investigate the mechanisms underlying RTK specificity in craniofacial development, we performed RNA-seq to delineate the transcriptional response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling in mouse embryonic palatal mesenchyme cells. While the early gene expression profile induced by both growth factors is qualitatively similar, the late response is divergent. Comparing the effect of MEK (Mitogen/Extracellular signal-regulated kinase) and PI3K (phosphoinositide-3-kinase) inhibition, we find the FGF response is MEK dependent, while the PDGF response is PI3K dependent. Furthermore, FGF promotes proliferation but PDGF favors differentiation. Finally, we demonstrate overlapping domains of PDGF-PI3K signaling and osteoblast differentiation in the palate and increased osteogenesis in FGF mutants, indicating this differentiation circuit is conserved in vivo. Our results identify distinct responses to PDGF and FGF and provide insight into the mechanisms encoding RTK specificity. DOI: http://dx.doi.org/10.7554/eLife.07186.001 Cells produce many different proteins that play a variety of important roles. For example, proteins called receptor tyrosine kinases can detect particular molecules and send signals to other parts of the cell to regulate the activity (or “expression”) of genes involved in cell division, movement, and other processes. Humans have 58 receptor tyrosine kinases, and defects in these proteins have been linked to diseases such as cancer and diabetes. However, many different receptors regulate the activities of shared sets of genes, so it is not clear how an individual receptor can specifically control the genes involved in a particular process. Two receptor tyrosine kinases called PDGFR and FGFR are crucial for the development of the face, palate, and head in humans and other animals. Vasudevan et al. used a technique called RNA-sequencing to find out which genes are regulated by these receptors in mouse palate cells. The experiments show that there is a common set of genes whose activities change quickly—within 1 hour—in response to the activation of either PDGFR or FGFR. However, several hours later, cells in which PDGFR is activated have different patterns of gene expression compared to those with active FGFR. Vasudevan et al. also found that FGFR promotes cell division, while PDGFR promotes the changing of palate cells into different types with more specialized roles. These different outcomes arise because PDGFR and FGFR use different signaling pathways that involve distinct proteins. For example, a protein called PI3K is critical for changes in gene expression in response to PDGFR but not FGFR. These results suggest that PGDRF and FGFR control different cellular processes in the palate by sending distinct signals into the cell. Understanding the receptor tyrosine kinases and the networks of genes they activate will help us to identify the signals that are important for other processes, such as the development of the face. DOI: http://dx.doi.org/10.7554/eLife.07186.002