The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1
The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1
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DOI：
10.1111/j.1365-2443.2005.00886.x
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发表时间：
2005-09-01
期刊：
影响因子：
2.1
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
--
作者：
Nonami, A;Taketomi, T;Yoshimura, A
Caveolin-1（Cav-1）在多种细胞类型中被认为是丝裂原刺激的增殖和Ras-p42/44 ERK（MAP激酶）通路的负调节剂。然而，这种抑制的分子基础尚未阐明。Spred/Sprouty家族蛋白也是ERK途径的负调节因子，通过与Raf-1相互作用。Spred/Sprouty家族蛋白在C-末端含有富含半胱氨酸（CR）的结构域，其被认为像Cav-1一样被棕榈酰化并且是膜锚定所必需的。在这项研究中，我们证明，Spred-1定位在富含胆固醇的膜筏/小窝馏分和相互作用的Cav-1。为了阐明Cav-1/Spred-1相互作用的生物学效应，我们使用缺乏小窝蛋白表达但表达Spred-1的造血细胞。Cav-1的强制表达抑制SCF和IL-3诱导的增殖和ERK激活。此外，在Cav-1表达细胞中强制表达外源性Spred-1进一步抑制增殖和ERK激活。这些数据表明Spred-1与Cav-1协同抑制ERK活化。
Caveolin-1 (Cav-1) has been suggested to function as a negative regulator of mitogen-stimulated proliferation and the Ras-p42/44 ERK (MAP kinase) pathway in a variety of cell types. However, the molecular basis of this suppression has not been clarified. Spred/Sprouty family proteins are also negative regulators of the ERK pathway by interacting with Raf-1. The Spred/Sprouty family proteins contain a cysteine-rich (CR) domain at the C-terminus, which is thought to be palmitoylated like Cav-1 and necessary for membrane anchoring. In this study, we demonstrated that Spred-1 localized in cholesterol-rich membrane raft/caveola fractions and interacted with Cav-1. To clarify the biological effect of Cav-1/Spred-1 interaction, we used hematopoietic cells that lacked expression of caveolins but expressed Spred-1. Forced expression of Cav-1 suppressed SCF- and IL-3-induced proliferation and ERK activation. Furthermore, forced expression of exogenous Spred-1 in Cav-1-expressing cells further suppressed proliferation and ERK activation. These data suggest that Spred-1 inhibits ERK activation in collaboration with Cav-1.