Sakamoto O, Iwama A, Amitani R, Takehara T, Yamaguchi N, Yamamoto T, Masuyama K, Yamanaka T, Ando M, Suda T
Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan.
J Clin Invest. 1997 Feb 15;99(4):701-9. doi: 10.1172/JCI119214.
Macrophage-stimulating protein (MSP) is an 80-kD serum protein with homology to hepatocyte growth factor (HGF). Its receptor, RON tyrosine kinase, is a new member of the HGF receptor family. The MSP-RON signaling pathway has been implicated in the functional regulation of mononuclear phagocytes. However, the function of this pathway in other types of cells has not been elucidated. Here we show that in contrast to the HGF receptor, which was expressed at the basolateral surface, RON was localized at the apical surface of ciliated epithelia in the airways and oviduct. In addition, MSP was found in the bronchoalveolar space at biologically significant concentrations. MSP bound to RON on normal human bronchial epithelial cells with a high affinity (Kd = 0.5 nM) and induced autophosphorylation of RON. Activation of RON by MSP led to a significant increase in ciliary beat frequency of human nasal cilia. These findings indicate that the ciliated epithelium of the mucociliary transport apparatus is a novel target of MSP. Ciliary motility is critical for mucociliary transport. Our findings suggest that the MSP-RON signaling pathway is a novel regulatory system of mucociliary function and might be involved in the host defense and fertilization.
巨噬细胞刺激蛋白（MSP）是一种80kD的血清蛋白，与肝细胞生长因子（HGF）具有同源性。其受体RON酪氨酸激酶是HGF受体家族的新成员。MSP-RON信号通路与单核吞噬细胞的功能调节有关。然而，该通路在其他类型细胞中的功能尚未阐明。在这里，我们发现，与表达于基底外侧表面的HGF受体不同，RON定位于气道和输卵管纤毛上皮的顶端表面。此外，在支气管肺泡腔中发现了具有生物学意义浓度的MSP。MSP以高亲和力（Kd = 0.5 nM）与正常人支气管上皮细胞上的RON结合，并诱导RON的自磷酸化。MSP激活RON导致人鼻纤毛的纤毛摆动频率显著增加。这些发现表明，黏液纤毛转运装置的纤毛上皮是MSP的一个新靶点。纤毛运动对黏液纤毛转运至关重要。我们的发现表明，MSP-RON信号通路是黏液纤毛功能的一个新的调节系统，可能参与宿主防御和受精过程。
