Muhl Lars, Folestad Erika Bergsten, Gladh Hanna, Wang Yixin, Moessinger Christine, Jakobsson Lars, Eriksson Ulf
Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Scheeles väg 2, A3:P4, Stockholm S-17177, Sweden
Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Scheeles väg 2, A3:P4, Stockholm S-17177, Sweden.
J Cell Sci. 2017 Apr 15;130(8):1365-1378. doi: 10.1242/jcs.200493. Epub 2017 Mar 2.
Platelet-derived growth factor (PDGF)-D is a PDGF receptor β (PDGFRβ)-specific ligand implicated in a number of pathological conditions, such as cardiovascular disease and cancer, but its biological function remains incompletely understood. In this study, we demonstrate that PDGF-D binds directly to neuropilin 1 (NRP1), in a manner that requires the PDGF-D C-terminal Arg residue. Stimulation with PDGF-D, but not PDGF-B, induced PDGFRβ-NRP1 complex formation in fibroblasts. Additionally, PDGF-D induced translocation of NRP1 to cell-cell junctions in endothelial cells, independently of PDGFRβ, altering the availability of NRP1 for VEGF-A-VEGFR2 signaling. PDGF-D showed differential effects on pericyte behavior in sprouting assays compared to PDGF-B. Furthermore, PDGF-D-induced PDGFRβ-NRP1 interaction can occur in between molecules located in different cells (endothelial cells and pericytes). In summary, we show that NRP1 can act as a co-receptor for PDGF-D-PDGFRβ signaling and is possibly implicated in intercellular communication in the vascular wall.
血小板衍生生长因子（PDGF）-D是一种特异性作用于血小板衍生生长因子受体β（PDGFRβ）的配体，与多种病理状况有关，如心血管疾病和癌症，但其生物学功能仍未完全明确。在本研究中，我们证明PDGF-D以一种依赖于PDGF-D C末端精氨酸残基的方式直接与神经纤毛蛋白1（NRP1）结合。用PDGF-D而非PDGF-B刺激可诱导成纤维细胞中形成PDGFRβ-NRP1复合物。此外，PDGF-D可诱导内皮细胞中的NRP1转位至细胞间连接，这一过程独立于PDGFRβ，从而改变NRP1对血管内皮生长因子A（VEGF-A）-血管内皮生长因子受体2（VEGFR2）信号传导的可用性。在发芽试验中，与PDGF-B相比，PDGF-D对周细胞行为表现出不同的影响。此外，PDGF-D诱导的PDGFRβ-NRP1相互作用可发生在位于不同细胞（内皮细胞和周细胞）中的分子之间。总之，我们表明NRP1可作为PDGF-D-PDGFRβ信号传导的共受体，并可能参与血管壁中的细胞间通讯。
