γ-Secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1.
γ-Secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1.
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DOI：
10.1074/jbc.m111.296590
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发表时间：
2011-12-09
期刊：
影响因子：
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通讯作者：
Boulton ME
中科院分区：
文献类型：
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作者：
Cai J;Chen Z;Ruan Q;Han S;Liu L;Qi X;Boye SL;Hauswirth WW;Grant MB;Boulton ME
背景：γ-分泌酶调节VEGFR 1信号传导。结果：VEGFR 1的跨膜切割发生在缬氨酸767处，激活的VEGFR 1的VE-PTP去磷酸化需要全长早老素1。结论：γ-Secretase切割VEGFR 1，全长早老素是VEGFR 1去磷酸化的关键衔接分子。重要性：更好地了解PEDF介导的VEGFR 1信号传导以及γ-分泌酶/早老素在血管生成调节中的作用对于细胞生物学非常重要。我们以前曾报道过色素上皮衍生因子（PEDF）可以通过γ-分泌酶介导的事件抑制VEGF诱导的微血管内皮细胞中的血管生成，其作用包括（a）切割和胞内转位VEGF受体-1（VEGFR 1）的C-末端片段和（B）抑制VEGF诱导的VEGFR 1磷酸化。使用位点直接诱变和转染的野生型和突变的受体到内皮细胞，我们表明，VEGFR 1的跨膜切割发生在缬氨酸767和开关从缬氨酸丙氨酸在这个位置防止切割和形成的VEGFR 1细胞内片段。使用siRNA选择性敲低内皮细胞中的蛋白酪氨酸磷酸酶（PTP），我们证明了血管内皮PTP负责活化的VEGFR 1的去磷酸化。PEDF上调全长早老素1（Fl. PS1）促进血管内皮PTP和VEGFR 1的关联。Fl.PS1的敲低阻止VEGFR 1的去磷酸化，而Fl.PS1的上调刺激VEGFR 1的去磷酸化。在PEDF处理后15分钟内，Fl.PS1与VEGFR 1相关。总之，我们确定了负责VEGFR 1信号转导的PEDF介导的事件，并确定了全长早老素作为VEGFR 1去磷酸化的关键衔接分子。对VEGFR 1信号调节的更深入理解将有助于确定新的抗VEGF治疗策略。
Background: γ-Secretase regulates VEGFR1 signaling. Results: Transmembrane cleavage of VEGFR1 occurs at valine 767, and VE-PTP dephosphorylation of activated VEGFR1 requires full-length presenilin 1. Conclusion: γ-Secretase cleaves VEGFR1, and full-length presenilin is a critical adaptor molecule in the dephosphorylation of VEGFR1. Significance: A greater understanding of PEDF-mediated VEGFR1 signaling and the role of γ-secretase/presenilin in the regulation of angiogenesis is important for cell biology. We have reported previously that pigment epithelium-derived factor (PEDF) can, via γ-secretase-mediated events, inhibit VEGF-induced angiogenesis in microvascular endothelial cells by both (a) cleavage and intracellular translocation of a C-terminal fragment of VEGF receptor-1 (VEGFR1) and (b) inhibition of VEGF-induced phosphorylation of VEGFR1. Using site-direct mutagenesis and transfection of wild type and mutated receptors into endothelial cells, we showed that transmembrane cleavage of VEGFR1 occurs at valine 767 and that a switch from valine to alanine at this position prevented cleavage and formation of a VEGFR1 intracellular fragment. Using siRNA to selectively knock down protein-tyrosine phosphatases (PTPs) in endothelial cells, we demonstrated that vascular endothelial PTP is responsible for dephosphorylation of activated VEGFR1. PEDF up-regulation of full-length presenilin 1 (Fl.PS1) facilitated the association of vascular endothelial PTP and VEGFR1. Knockdown of Fl.PS1 prevented dephosphorylation of VEGFR1, whereas up-regulation of Fl.PS1 stimulated VEGFR1 dephosphorylation. Fl.PS1 associated with VEGFR1 within 15 min after PEDF treatment. In conclusion, we determined the PEDF-mediated events responsible for VEGFR1 signaling and identified full-length presenilin as a critical adaptor molecule in the dephosphorylation of VEGFR1. This greater understanding of the regulation of VEGFR1 signaling will help identify novel anti-VEGF therapeutic strategies.