Metalloproteinase/presenilin 1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling
Metalloproteinase/presenilin 1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling
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DOI：
10.1038/sj.emboj.7601031
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发表时间：
2006-03-22
期刊：
影响因子：
11.4
通讯作者：
Robakis, NK
中科院分区：
文献类型：
--
作者：
Georgakopoulos, A;Litterst, C;Robakis, NK
由EphB受体和EphB配体相互作用所触发的双向信号对血管和神经系统的发育和功能是至关重要的。由这种相互作用触发的信号级联涉及到Src激酶的激活和eaffinB的磷酸化。然而，EphB激活表达EphinB的细胞中的Src的机制尚不清楚。在这里，我们证明了EphB刺激金属蛋白酶裂解ewitinB2，产生一个羧基末端片段，该片段进一步被PS1/伽马分泌酶处理，产生胞内肽ewitinB2/CTF2。该多肽结合Src并抑制其与抑制激酶CSK的结合，允许在Tyr418残基上自动磷酸化Src。ElearinB2/CTF2激活的Src通过c-分泌酶磷酸化ewitinB2并抑制其加工。这些数据表明，PS1/γ-分泌酶系统通过调节Src激活剂ewitinB2/CTF2的产生来控制Src的激活和ewitinB的磷酸化。因此，伽马分泌酶抑制剂阻止了EphB诱导的内皮细胞的萌发和Grb4对ePhinB的募集。Ps1、Fad和γ-分泌酶显性负性突变体抑制了EphB诱导的ewitinB2的裂解和Src的自磷酸化，增加了Fad突变体干扰中枢神经系统中src和ewitinB2功能的可能性。
Bidirectional signaling triggered by interacting ephrinB receptors (EphB) and ephrinB ligands is crucial for development and function of the vascular and nervous systems. A signaling cascade triggered by this interaction involves activation of Src kinase and phosphorylation of ephrinB. The mechanism, however, by which EphB activates Src in the ephrinB-expressing cells is unknown. Here we show that EphB stimulates a metalloproteinase cleavage of ephrinB2, producing a carboxy-terminal fragment that is further processed by PS1/gamma-secretase to produce intracellular peptide ephrinB2/CTF2. This peptide binds Src and inhibits its association with inhibitory kinase Csk, allowing autophosphorylation of Src at residue tyr418. EphrinB2/CTF2-activated Src phosphorylates ephrinB2 and inhibits its processing by c-secretase. These data show that the PS1/gamma-secretase system controls Src activation and ephrinB phosphorylation by regulating production of Src activator ephrinB2/CTF2. Accordingly, gamma-secretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB. PS1 FAD and gamma-secretase dominant-negative mutants inhibited the EphB-induced cleavage of ephrinB2 and Src autophosphorylation, raising the possibility that FAD mutants interfere with the functions of Src and ephrinB2 in the CNS.