Expression of kindlin-3 in melanoma cells impedes cell migration and metastasis

Kindlins are a small family of 4.1-ezrin-radixin-moesin (FERM)-containing cytoplasmic proteins. Kindlin-3 is expressed in platelets, hematopoietic cells, and endothelial cells. Kindlin-3 promotes integrin activation, clustering and outside-in signaling. Aberrant expression of kindlin-3 was reported in melanoma and breast cancer. Intriguingly, kindlin-3 has been reported to either positively or negatively regulate cancer cell metastasis. In this study, we sought to clarify the expression of kindlin-3 in melanoma cells and its role in melanoma metastasis. Two widely used metastatic mouse and human melanoma cell lines B16-F10 and M10, respectively, were examined and found to lack kindlin-3 mRNA and protein expression. When kindlin-3 was ectopically expressed in these cells, cell migration was markedly reduced. These are attributed to aberrant Rac1 and RhoA activation and overt membrane ruffling. Our data demonstrate for the first time that despite its well established role as a positive regulator of integrin-mediated cell adhesion, aberrant expression of kindlin-3 could lead to imbalanced RhoGTPases signaling that impedes rather than promotes cell migration.

Kindlin蛋白家族是一类小型胞质蛋白家族，所有成员均携带有4.1-埃兹蛋白-根蛋白-膜突蛋白（FERM）结构域。Kindlin-3表达于血小板、造血细胞及内皮细胞中，可促进整合素的活化、聚集以及外向信号转导（outside-in signaling）。已有研究显示，Kindlin-3的异常表达可见于黑色素瘤与乳腺癌组织；值得注意的是，该蛋白对癌细胞转移兼具正向与负向调控作用。本研究旨在明确Kindlin-3在黑色素瘤细胞中的表达特征，及其在黑色素瘤转移过程中的调控功能。本研究分别对两种经典的转移性黑色素瘤细胞系——小鼠源B16-F10与人类源M10进行检测，结果发现二者均不表达Kindlin-3的mRNA与蛋白。当在上述细胞系中异位表达Kindlin-3后，细胞的迁移能力显著降低，该效应可归因于Rac1与RhoA的异常活化，以及显著的膜褶皱形成。本研究数据首次证实：尽管Kindlin-3作为整合素介导的细胞黏附正向调控因子的功能已得到广泛认可，但其异常表达可导致Rho家族小GTP酶（RhoGTPases）信号通路失衡，反而抑制而非促进细胞迁移。