Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation
Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation
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DOI：
10.1074/jbc.m600298200
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发表时间：
2006-04-14
影响因子：
4.8
通讯作者：
Weinmaster, G
中科院分区：
文献类型：
--
作者：
Miyamoto, A;Lau, R;Weinmaster, G
与大多数受体不同，Notch既是信号事件的接收器，也是信号事件的直接转导器。激活可由Delta样（-1，-2，-4）或Jagged/Serrate（-1，-2）家族的五种膜结合配体之一介导。或者，Notch异二聚体的解离以及随后的活化也可以通过钙螯合剂或通过使Notch 1异二聚体不稳定的突变（例如在人类疾病T细胞急性淋巴细胞白血病中）来实验性地介导。在这里，我们表明，MAGP-2，微纤维上存在的蛋白质，也可以与EGF样重复的Notch 1相互作用。MAGP-2与Notch 1的共表达导致Notch 1胞外域的细胞表面释放和随后的Notch信号传导激活。此外，我们证明了MAGP-2的C-末端结构域是Notch 1结合和激活所必需的。基于高水平的同源性，我们预测并进一步表明MAGP-1也可以与Notch 1结合，引起胞外结构域的释放，并激活信号传导。由MAGP-2诱导的Notch 1胞外结构域释放依赖于通过弗林蛋白酶样切割形成Notch 1异源二聚体，但不需要随后的生成Notch信号片段所必需的ADAM金属蛋白酶切割。这些结果一起首次证明了微纤维蛋白MAGP-1和MAGP-2可以在弹性纤维中的作用之外发挥作用，以激活细胞信号传导途径。
Unlike most receptors, Notch serves as both the receiver and direct transducer of signaling events. Activation can be mediated by one of five membrane-bound ligands of either the Delta-like (-1, -2, -4) or Jagged/Serrate (-1, -2) families. Alternatively, dissociation of the Notch heterodimer with consequent activation can also be mediated experimentally by calcium chelators or by mutations that destabilize the Notch1 heterodimer, such as in the human disease T cell acute lymphoblastic leukemia. Here we show that MAGP-2, a protein present on microfibrils, can also interact with the EGF-like repeats of Notch1. Co-expression of MAGP-2 with Notch1 leads to both cell surface release of the Notch1 extracellular domain and subsequent activation of Notch signaling. Moreover, we demonstrate that the C-terminal domain of MAGP-2 is required for binding and activation of Notch1. Based on the high level of homology, we predicted and further showed that MAGP-1 can also bind to Notch1, cause the release of the extracellular domain, and activate signaling. Notch1 extracellular domain release induced by MAGP-2 is dependent on formation of the Notch1 heterodimer by a furin-like cleavage, but does not require the subsequent ADAM metalloprotease cleavage necessary for production of the Notch signaling fragment. Together these results demonstrate for the first time that the microfibrillar proteins MAGP-1 and MAGP-2 can function outside of their role in elastic fibers to activate a cellular signaling pathway.