The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis

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• 作者：Anthony Lanahan¹ ; ⁵ ; Xi Zhang¹ ; ² ; ⁵ ; Alessandro Fantin³ ; Zhen Zhuang¹ ; Felix Rivera-Molina² ; Katherine Speichinger⁴ ; Claudia Prahst¹ ; Jiasheng Zhang¹ ; Yingdi Wang¹ ; George Davis⁴ ; Derek Toomre² ; Christiana Ruhrberg¹ ; ³ ; ^{c.ruhrberg@ucl.ac.uk} ; Michael Simons¹ ; ² ; ^{michael.simons@yale.edu}
• 刊名：Developmental Cell
• 出版年：2013
• 出版时间：29 April, 2013
• 年：2013
• 卷：25
• 期：2
• 页码：156-168
• 全文大小：2210 K

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Summary

Neuropilin 1 (NRP1) plays an important but ill-defined role in VEGF-A signaling and vascular morphogenesis. We show that mice with a knockin mutation that ablates the NRP1 cytoplasmic tail (Nrp1^cyto) have normal angiogenesis but impaired developmental and adult arteriogenesis. The arteriogenic defect was traced to the absence of a PDZ-dependent interaction between NRP1 and VEGF receptor 2 (VEGFR2) complex and synectin, which delayed trafficking of endocytosed VEGFR2 from Rab5+ to EAA1+ endosomes. This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y¹¹⁷⁵, the site involved in activating ERK signaling. The Nrp1^cyto mutation also impaired endothelial tubulogenesis in?vitro, which could be rescued by expressing full-length NRP1 or constitutively active ERK. These results demonstrate that the NRP1 cytoplasmic domain promotes VEGFR2 trafficking in a PDZ-dependent manner to regulate arteriogenic ERK signaling and establish a role for NRP1 in VEGF-A signaling during vascular morphogenesis.