Prag Søren, Lepekhin Eugene A, Kolkova Kateryna, Hartmann-Petersen Rasmus, Kawa Anna, Walmod Peter S, Belman Vadym, Gallagher Helen C, Berezin Vladimir, Bock Elisabeth, Pedersen Nina
Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Denmark.
J Cell Sci. 2002 Jan 15;115(Pt 2):283-92. doi: 10.1242/jcs.115.2.283.
Cell migration is required during development of the nervous system. The regulatory mechanisms for this process, however, are poorly elucidated. We show here that expression of or exposure to the neural cell adhesion molecule (NCAM) strongly affected the motile behaviour of glioma cells independently of homophilic NCAM interactions. Expression of the transmembrane 140 kDa isoform of NCAM (NCAM-140) caused a significant reduction in cellular motility, probably through interference with factors regulating cellular attachment, as NCAM-140-expressing cells exhibited a decreased attachment to a fibronectin substratum compared with NCAM-negative cells. Ectopic expression of the cytoplasmic part of NCAM-140 also inhibited cell motility, presumably via the non-receptor tyrosine kinase p59(fyn) with which NCAM-140 interacts. Furthermore, we showed that the extracellular part of NCAM acted as a paracrine inhibitor of NCAM-negative cell locomotion through a heterophilic interaction with a cell-surface receptor. As we showed that the two N-terminal immunoglobulin modules of NCAM, which are known to bind to heparin, were responsible for this inhibition, we presume that this receptor is a heparan sulfate proteoglycan. A model for the inhibitory effect of NCAM is proposed, which involves competition between NCAM and extracellular components for the binding to membrane-associated heparan sulfate proteoglycan.
在神经系统发育过程中，细胞迁移是必需的。然而，这一过程的调控机制尚未得到充分阐明。我们在此表明，神经细胞黏附分子（NCAM）的表达或暴露会强烈影响胶质瘤细胞的运动行为，且与同型NCAM相互作用无关。NCAM跨膜140 kDa异构体（NCAM-140）的表达导致细胞运动性显著降低，这可能是通过干扰调节细胞黏附的因子实现的，因为与NCAM阴性细胞相比，表达NCAM-140的细胞对纤连蛋白基质的黏附能力下降。NCAM-140胞质部分的异位表达也抑制细胞运动，推测是通过与NCAM-140相互作用的非受体酪氨酸激酶p59(fyn)介导的。此外，我们表明NCAM的细胞外部分通过与细胞表面受体的异嗜性相互作用，作为NCAM阴性细胞运动的旁分泌抑制剂。由于我们发现已知与肝素结合的NCAM的两个N端免疫球蛋白模块负责这种抑制作用，我们推测该受体是硫酸乙酰肝素蛋白聚糖。我们提出了一个NCAM抑制作用的模型，该模型涉及NCAM与细胞外成分之间竞争与膜相关硫酸乙酰肝素蛋白聚糖的结合。
