Sprouty proteins: antagonists of endothelial cell signaling and more
Sprouty proteins: antagonists of endothelial cell signaling and more
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DOI：
10.1160/th03-04-0217
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发表时间：
2003-10-01
影响因子：
6.7
通讯作者：
Christofori, G
中科院分区：
文献类型：
--
作者：
Cabrita, MA;Christofori, G
在众多的信号通路中，受体酪氨酸激酶（RTK）可以激活丝裂原活化蛋白激酶（MAPK）信号通路，该信号通路随后导致多种细胞变化，包括增殖、分化和运动。生长因子信号传导的调节是复杂的，并且各种细胞类型对相同刺激的反应不同，原因尚不完全清楚。最近在果蝇中发现的Sprouty（dSpry）是RTK诱导的MAPK激活的抑制剂，为这些信号如何调节提供了线索。在哺乳动物中，四个直向同源的dSpry，Spry 1-4，已被描述，在这篇综述中，我们讨论他们的功能特点。哺乳动物Spry，如dSpry，是许多生长因子受体的配体诱导的反馈抑制剂。在内皮细胞中，当成纤维细胞生长因子（FGF）受体和血管内皮生长因子（VEGF）受体活化时，Sprys易位至质膜并抑制细胞生长和增殖。然而，在表皮生长因子（EGF）刺激的细胞中，Sprys可以增强MAPK的激活。此外，Sprys具有许多结合伴侣，包括MAPK活化途径的不同效应物。Sprys干扰MAPK通路的交叉点以及它们与其他蛋白质的相互作用可以部分解释生长因子诱导的MAPK活化的双重但相反的作用。此外，Sprys需要酪氨酸磷酸化与其结合伴侣相互作用，这是其双重功能的先决条件。因此，Sprys为RTK介导的信号转导调节增加了另一层复杂性，这开始解释细胞对生长因子反应的变化。
Among many signaling pathways, receptor tyrosine kinases (RTKs) can activate the mitogen-activated protein kinase (MAPK) signaling pathway that subsequently leads to a variety of cellular changes, including proliferation, differentiation and motility. The regulation of growth factor signaling is complex, and various cell types respond differently to the same stimulus for reasons not entirely understood. The recent discovery in Drosophila of Sprouty (dSpry), an inhibitor of RTK-induced MAPK activation, provides clues to how these signals are regulated. In mammals, four orthologues of dSpry, Spry 1-4, have been described, and in this review we discuss their functional characteristics. Mammalian Sprys, like dSpry, are ligand-induced feedback inhibitors of a number of growth factor receptors. In endothelial cells, upon fibroblast growth factor (FGF) receptor and vascular endothelial growth factor (VEGF) receptor activation, Sprys translocate to the plasma membrane and inhibit cell growth and proliferation. However, in epidermal growth factor (EGF)-stimulated cells, Sprys can enhance MAPK activation. In addition, Sprys have many binding partners, including different effectors of the MAPK activation pathway. The intersection point where Sprys interfere in the MAPK pathway as well as their interactions with other proteins may partly explain the dual, yet opposing roles, on growth factor-induced MAPK activation. Moreover, Sprys require tyrosine phosphorylation to interact with their binding partners, a prerequisite for their dual function. Hence, Sprys add another layer of complexity to the regulation of RTK-mediated signal transduction that begins to explain the variation in cellular responses to growth factors.