Institute for Cancer Research at Candiolo, IRC@C, and University of Torino Medical School, Candiolo, Italy.
Cancer Res. 2012 Nov 15;72(22):5801-11. doi: 10.1158/0008-5472.CAN-12-0995. Epub 2012 Sep 17.
Neuropilin-1 (NRP1) is a coreceptor for multiple extracellular ligands. NRP1 is widely expressed in cancer cells and in advanced human tumors; however, its functional relevance and signaling mechanisms are unclear. Here, we show that NRP1 expression controls viability and proliferation of different cancer cells, independent of its short intracellular tail. We found that the extracellular domain of NRP1 interacts with the EGF receptor (EGFR) and promotes its signaling cascade elicited upon EGF or TGF-α stimulation. Upon NRP1 silencing, the ability of ligand-bound EGFR to cluster on the cell surface, internalize, and activate the downstream AKT pathway is severely impaired. EGFR is frequently activated in human tumors due to overexpression, mutation, or sustained autocrine/paracrine stimulation. Here we show that NRP1-blocking antibodies and NRP1 silencing can counteract ligand-induced EGFR activation in cancer cells. Thus our findings unveil a novel molecular mechanism by which NRP1 can control EGFR signaling and tumor growth.
神经纤毛蛋白 1（NRP1）是多种细胞外配体的核心受体。NRP1 在癌细胞和晚期人类肿瘤中广泛表达，但它的功能相关性和信号机制尚不清楚。在这里，我们表明 NRP1 的表达控制着不同癌细胞的活力和增殖，而不依赖于其短的细胞内尾巴。我们发现 NRP1 的细胞外结构域与表皮生长因子受体（EGFR）相互作用，并促进 EGFR 在 EGF 或 TGF-α刺激下的信号级联反应。沉默 NRP1 后，配体结合的 EGFR 在细胞表面聚集、内化和激活下游 AKT 途径的能力严重受损。由于过度表达、突变或持续的自分泌/旁分泌刺激，EGFR 在人类肿瘤中经常被激活。在这里，我们表明 NRP1 阻断抗体和 NRP1 沉默可以拮抗配体诱导的癌细胞中 EGFR 的激活。因此，我们的研究结果揭示了 NRP1 控制 EGFR 信号和肿瘤生长的一种新的分子机制。
