Lanahan, A; Zhang, X; Fantin, A; Zhuang, Z; Rivera-Molina, F; Speichinger, K; Prahst, C; ... Simons, M; + view all Lanahan, A; Zhang, X; Fantin, A; Zhuang, Z; Rivera-Molina, F; Speichinger, K; Prahst, C; Zhang, J; Wang, Y; Davis, G; Toomre, D; Ruhrberg, C; Simons, M; - view fewer (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell , 25 (2) 156 - 168. 10.1016/j.devcel.2013.03.019.

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Abstract

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 Y(1175), 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.

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