The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface
The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface
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DOI：
10.1074/jbc.m500273200
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发表时间：
2005-05-27
影响因子：
4.8
通讯作者：
Shipley, JM
中科院分区：
文献类型：
--
作者：
Nehring, LC;Miyamoto, A;Shipley, JM
弹性纤维由蛋白质弹性蛋白和10-12 nm的微纤维网络组成，微纤维由几种糖蛋白组成，包括纤维蛋白-1、纤维蛋白-2和MAGP1/2(微原纤维相关的糖蛋白-1和-2)。虽然纤维蛋白和MAGP是共价结合的，但我们发现DSL(Delta/Serrate/LAG2)蛋白Jagged1是Notch受体信号转导的激活配体，在酵母双杂交和免疫共沉淀研究中也与MAGP-2相互作用。Jagged1和MAGP-2之间的相互作用需要Jagged1的表皮生长因子样重复序列。共表达全长Jagged1和MAGP-2的293T细胞和COS-7细胞的Jagged1胞外区与MAGP-2形成复合体。金属蛋白酶异构体抑制剂BB3103可减少Jagged1胞外区MAGP-2的脱落，提示其释放与蛋白水解酶有关。虽然MAGP-2也与其他DSL配体Jagged2和Delta1相互作用，但在条件培养液中没有发现它们与MAGP-2相关，从而确定了MAGP-2对DSL配体脱落的不同影响。相关的微纤维蛋白MAGP-1也被发现与DSL配体相互作用，但与MAGP-2不同的是，它不能促进Jagged1的脱落。我们的发现表明，除了在微纤维中的作用外，MAGP-2还可能通过与细胞表面DSL配体结合或通过促进可溶性胞外形式的Jagged1的释放和/或稳定来调节Notch信号通路，从而影响细胞分化。
Elastic fibers are composed of the protein elastin and a network of 10-12-nm microfibrils, which are composed of several glycoproteins, including fibrillin-1, fibrillin-2, and MAGP1/2 (microfibril-associated glycoproteins-1 and -2). Although fibrillins and MAGPs covalently associate, we find that the DSL (Delta/Serrate/LAG2) protein Jagged1, an activating ligand for Notch receptor signaling, also interacts with MAGP-2 in both yeast two-hybrid and coimmunoprecipitation studies. Interaction between Jagged1 and MAGP-2 requires the epidermal growth factor-like repeats of Jagged1. MAGP-2 was found complexed with the Jagged1 extracellular domain shed from 293T cells and COS-7 cells coexpressing full-length Jagged1 and MAGP-2. MAGP- 2 shedding of the Jagged1 extracellular domain was decreased by the metalloproteinase hydroxamate inhibitor BB3103 implicating proteolysis in its release. Although MAGP- 2 also interacted with the other DSL ligands, Jagged2 and Delta1, they were not found associated with MAGP-2 in the conditioned media, identifying differential effects of MAGP- 2 on DSL ligand shedding. The related microfibrillar protein MAGP- 1 was also found to interact with DSL ligands but, unlike MAGP-2, was unable to facilitate the shedding of Jagged1. Our findings suggest that in addition to its role in microfibrils, MAGP-2 may also affect cellular differentiation through modulating the Notch signaling pathway either by binding to cell surface DSL ligands or by facilitating release and/or stabilization of a soluble extracellular form of Jagged1.