Santoro Massimo M, Gaudino Giovanni, Marchisio Pier Carlo
Department of Medical Sciences, University of Piemonte Orientale "A. Avogadro", 28100, Novara, Italy.
Dev Cell. 2003 Aug;5(2):257-71. doi: 10.1016/s1534-5807(03)00201-6.
Growth factors, integrins, and the extracellular matrix (ECM) are known to play key roles in epidermal wound healing, although the interplay between these proteins is not fully understood. We show that growth factor macrophage stimulating protein (MSP)- and its receptor Ron-mediated PI3K activation in keratinocytes induces phosphorylation of both Ron and alpha6beta4 integrin at specific 14-3-3 binding sites. Consequently, a Ron/alpha6beta4 complex formed via 14-3-3 binding displaces alpha6beta4 from its location at hemidesmosomes (structures supporting cell adhesion) and relocalizes it to lamellipodia. Concomitant activation of alpha3beta1 and keratinocyte spreading/migration on laminin-5 occurs. Further, MSP-dependent beta4 tyrosine phosphorylation evokes p38 and NF-kappaB signaling required for keratinocyte wound closure. Based on these results, we propose a mechanism based on MSP-Ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing.
生长因子、整合素和细胞外基质（ECM）在表皮伤口愈合中发挥关键作用，尽管这些蛋白质之间的相互作用尚未完全了解。我们发现，生长因子巨噬细胞刺激蛋白（MSP）及其受体Ron介导的角质形成细胞中的PI3K激活会诱导Ron和α6β4整合素在特定的14-3-3结合位点发生磷酸化。因此，通过14-3-3结合形成的Ron/α6β4复合物将α6β4从其在半桥粒（支持细胞粘附的结构）中的位置取代，并将其重新定位到片状伪足。同时，α3β1被激活，角质形成细胞在层粘连蛋白-5上扩散/迁移。此外，MSP依赖的β4酪氨酸磷酸化引发角质形成细胞伤口闭合所需的p38和NF-κB信号传导。基于这些结果，我们提出了一种基于MSP-Ron依赖的磷酸化和14-3-3结合的机制，据此α6β4的功能从机械粘附装置转变为信号成分，并可能在人类表皮伤口愈合中起关键作用。
