Podoplanin associates with CD44 to promote directional cell migration.
Podoplanin associates with CD44 to promote directional cell migration.
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DOI：
10.1091/mbc.e10-06-0489
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发表时间：
2010-12
影响因子：
3.3
通讯作者：
Quintanilla M
中科院分区：
文献类型：
--
作者：
Martín-Villar E;Fernández-Muñoz B;Parsons M;Yurrita MM;Megías D;Pérez-Gómez E;Jones GE;Quintanilla M
泊多拉宁是一种癌症相关糖蛋白，与CD44相互作用。这两种糖蛋白在肿瘤进展过程中协同上调。Pod-CD44在细胞膜上的相互作用主要发生在迁移的细胞中，它似乎是PodoPlanin介导的细胞迁移和方向性所必需的。泊多拉宁是一种跨膜糖蛋白，在不同的人类肿瘤中表达上调，尤其是来自鳞状复层上皮(SCCs)的肿瘤。它在肿瘤细胞中的表达与细胞迁移和侵袭力的增加有关；然而，这一过程背后的机制仍然知之甚少。在此，我们报道了主要的透明质酸(HA)受体CD44是泊多拉宁的新合作伙伴。在小鼠皮肤癌变模型中，CD44标准亚型(CD44s)的表达与泊多普兰蛋白的表达协同上调，在高侵袭性鳞癌的发生过程中，以及在上皮-间充质转化(EMT)过程中。在癌细胞中，CD44和泊多普宁共定位于细胞表面突起。此外，透明质酸包裹的微球或与特定的CD44抗体交联会促进CD44的募集，从而诱导泊多拉宁的共募集。免疫共沉淀实验和体内荧光共振能量转移/荧光寿命成像显微镜(FRET/FLIM)证实了泊多普宁-CD44s的相互作用，后者证实了它与具有迁移表型的细胞质膜上的联系。重要的是，我们还表明泊多拉宁促进上皮细胞运动的方向性持续，这是一个需要CD44的特征，并且这两个分子协同促进SCC细胞的方向性迁移。我们的结果支持CD44-泊多普兰相互作用在恶性肿瘤过程中驱动肿瘤细胞迁移的作用。
Podoplanin, a cancer-associated glycoprotein, interacts with CD44. Both glycoproteins are coordinately upregulated during tumor progression. Podoplanin–CD44 interaction in the cell membrane occurs mainly in migrating cells, and it seems to be required for podoplanin-mediated cell migration and directionality. Podoplanin is a transmembrane glycoprotein up-regulated in different human tumors, especially those derived from squamous stratified epithelia (SCCs). Its expression in tumor cells is linked to increased cell migration and invasiveness; however, the mechanisms underlying this process remain poorly understood. Here we report that CD44, the major hyaluronan (HA) receptor, is a novel partner for podoplanin. Expression of the CD44 standard isoform (CD44s) is coordinately up-regulated together with that of podoplanin during progression to highly aggressive SCCs in a mouse skin model of carcinogenesis, and during epithelial-mesenchymal transition (EMT). In carcinoma cells, CD44 and podoplanin colocalize at cell surface protrusions. Moreover, CD44 recruitment promoted by HA-coated beads or cross-linking with a specific CD44 antibody induced corecruitment of podoplanin. Podoplanin–CD44s interaction was demonstrated both by coimmunoprecipitation experiments and, in vivo, by fluorescence resonance energy transfer/fluorescence lifetime imaging microscopy (FRET/FLIM), the later confirming its association on the plasma membrane of cells with a migratory phenotype. Importantly, we also show that podoplanin promotes directional persistence of motility in epithelial cells, a feature that requires CD44, and that both molecules cooperate to promote directional migration in SCC cells. Our results support a role for CD44-podoplanin interaction in driving tumor cell migration during malignancy.