Monaghan-Benson Elizabeth, Mastick Cynthia Corley, McKeown-Longo Paula J
Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
J Cell Sci. 2008 Nov 15;121(Pt 22):3693-703. doi: 10.1242/jcs.028423. Epub 2008 Oct 28.
The relationship between the plasminogen activator system and integrin function is well documented but incompletely understood. The mechanism of uPAR-mediated signaling across the membrane and the molecular basis of uPAR-dependent activation of integrins remain important issues. The present study was undertaken to identify the molecular intermediates involved in the uPAR signaling pathway controlling alpha5beta1-integrin activation and fibronectin polymerization. Disruption of lipid rafts with MbetaCD or depletion of caveolin-1 by siRNA led to the inhibition of uPAR-dependent integrin activation and stimulation of fibronectin polymerization in human dermal fibroblasts. The data indicate a dual role for caveolin-1 in the uPAR signaling pathway, leading to integrin activation. Caveolin-1 functions initially as a membrane adaptor or scaffold to mediate uPAR-dependent activation of Src and EGFR. Subsequently, in its phosphorylated form, caveolin-1 acts as an accessory molecule to direct trafficking of activated EGFR to focal adhesions. These studies provide a novel paradigm for the regulation of crosstalk among integrins, growth-factor receptors and uPAR.
纤溶酶原激活物系统与整合素功能之间的关系已有充分记载，但尚未完全明确。uPAR介导的跨膜信号传导机制以及uPAR依赖性整合素激活的分子基础仍是重要问题。本研究旨在确定参与uPAR信号通路控制α5β1整合素激活和纤连蛋白聚合的分子中间体。用MβCD破坏脂筏或通过siRNA耗尽小窝蛋白-1可导致人皮肤成纤维细胞中uPAR依赖性整合素激活受到抑制，并刺激纤连蛋白聚合。数据表明小窝蛋白-1在uPAR信号通路中具有双重作用，导致整合素激活。小窝蛋白-1最初作为膜衔接蛋白或支架介导uPAR依赖性Src和EGFR激活。随后，以其磷酸化形式，小窝蛋白-1作为辅助分子将活化的EGFR转运至粘着斑。这些研究为整合素、生长因子受体和uPAR之间的串扰调节提供了新的范例。
