The tyrosine kinase c-Src directly mediates growth factor-induced Notch-1 and Furin interaction and Notch-1 activation in pancreatic cancer cells.
The tyrosine kinase c-Src directly mediates growth factor-induced Notch-1 and Furin interaction and Notch-1 activation in pancreatic cancer cells.
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酪氨酸激酶 c-Src 直接介导胰腺癌细胞中生长因子诱导的 Notch-1 和 Furin 相互作用以及 Notch-1 激活。
DOI：
10.1371/journal.pone.0033414
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang ZS
中科院分区：
文献类型：
--
作者：
Ma YC;Shi C;Zhang YN;Wang LG;Liu H;Jia HT;Zhang YX;Sarkar FH;Wang ZS
负责加工全长Notch-1 （p300）的Furin蛋白水解活性在Notch信号传导中起关键作用。Notch活性的振幅和持续时间可以在通路的各个点进行调节，但尽管Notch-1- furin相互作用很重要，但尚未有关于其调节的报道。在本研究中，我们发现Notch-1-Furin相互作用受非受体酪氨酸激酶c-Src的调控。c-Src和Notch-1在物理上是相关联的，这种关联负责Notch-1的处理和激活。我们还发现生长因子TGF-α（一种EGFR配体）和PDGF-BB（一种PDGFR配体）可诱导c-Src介导的Notch-1-Furin相互作用。我们的研究结果支持了三个新的和具有启动性的结论：(1)Notch-1和Furin之间的关联是一个调控良好的过程；(2)细胞外生长因子信号调节这种相互作用，这是由c-Src介导的；(3)血浆生长因子受体c- src与Notch通路之间存在串扰。Notch-1和c-Src的共定位在异种移植肿瘤组织和胰腺癌患者组织中得到证实。我们的研究结果揭示了Notch和生长因子受体c- src信号通路调节癌变和癌细胞生长的机制。
The proteolytic activity of Furin responsible for processing full length Notch-1 (p300) plays a critical role in Notch signaling. The amplitude and duration of Notch activity can be regulated at various points in the pathway, but there has been no report regarding regulation of the Notch-1-Furin interaction, despite its importance. In the present study, we found that the Notch-1-Furin interaction is regulated by the non-receptor tyrosine kinase, c-Src. c-Src and Notch-1 are physically associated, and this association is responsible for Notch-1 processing and activation. We also found that growth factor TGF-α, an EGFR ligand, and PDGF-BB, a PDGFR ligand, induce the Notch-1-Furin interaction mediated by c-Src. Our results support three new and provocative conclusions: (1) The association between Notch-1 and Furin is a well-regulated process; (2) Extracellular growth factor signals regulate this interaction, which is mediated by c-Src; (3) There is cross-talk between the plasma growth factor receptor-c-Src and Notch pathways. Co-localization of Notch-1 and c-Src was confirmed in xenograft tumor tissues and in the tissues of pancreatic cancer patients. Our findings have implications for the mechanism by which the Notch and growth factor receptor-c-Src signaling pathways regulate carcinogenesis and cancer cell growth.
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影响因子：
30.8
作者：
STIFANI, S;BLAUMUELLER, CM;ARTAVANISTSAKONAS, S
通讯作者：
ARTAVANISTSAKONAS, S
影响因子：
11.2
作者：
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Sarkar, FH
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21.3
作者：
Pulvirenti, Teodoro;Giannotta, Monica;Luini, Alberto
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影响因子：
64.5
作者：
Blaumueller, CM;Qi, HL;ArtavanisTsakonas, S
通讯作者：
ArtavanisTsakonas, S
影响因子：
64.8
作者：
Schroeter, EH;Kisslinger, JA;Kopan, R
通讯作者：
Kopan, R