Liu David, Aguirre Ghiso Julio, Estrada Yeriel, Ossowski Liliana
Department of Medicine, Division of Medical Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Cancer Cell. 2002 Jun;1(5):445-57. doi: 10.1016/s1535-6108(02)00072-7.
Urokinase plasminogen activator receptor (uPAR) activates alpha5beta1 integrin and ERK signaling, inducing in vivo proliferation of HEp3 human carcinoma. Here we demonstrate that EGFR mediates the uPAR/integrin/fibronectin (FN) induced growth pathway. Its activation is ligand-independent and does not require high EGFR, but does require high uPAR expression. Only when uPAR level is constitutively elevated does EGFR become alpha5beta1-associated and activated. Domain 1 of uPAR is crucial for EGFR activation, and FAK links integrin and EGFR signaling. Inhibition of EGFR kinase blocks uPAR induced signal to ERK, implicating EGFR as an important effector of the pathway. Disruption of uPAR or EGFR signaling reduces HEp3 proliferation in vivo. These findings unveil a mechanism whereby uPAR subverts ligand-regulated EGFR signaling, providing cancer cells with proliferative advantage.
尿激酶型纤溶酶原激活物受体（uPAR）激活α5β1整合素和ERK信号通路，诱导HEp3人癌细胞在体内增殖。在此我们证明，表皮生长因子受体（EGFR）介导uPAR/整合素/纤连蛋白（FN）诱导的生长途径。其激活不依赖配体，不需要高表达的EGFR，但确实需要高表达的uPAR。只有当uPAR水平持续升高时，EGFR才会与α5β1整合素结合并被激活。uPAR的结构域1对EGFR激活至关重要，黏着斑激酶（FAK）连接整合素和EGFR信号通路。抑制EGFR激酶可阻断uPAR诱导的ERK信号，这表明EGFR是该途径的重要效应器。破坏uPAR或EGFR信号通路可降低HEp3细胞在体内的增殖。这些发现揭示了一种机制，即uPAR颠覆配体调节的EGFR信号通路，为癌细胞提供增殖优势。
