Qu Jing, Ero Rya, Feng Chen, Ong Li-Teng, Tan Hui-Foon, Lee Hui-Shan, Ismail Muhammad H B, Bu Wen-Ting, Nama Srikanth, Sampath Prabha, Gao Yong-Gui, Tan Suet-Mien
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Institute of Medical Biology, 8A Biomedical Grove, Singapore 138648, Singapore.
Sci Rep. 2015 Dec 18;5:18491. doi: 10.1038/srep18491.
Kindlins are FERM-containing cytoplasmic proteins that regulate integrin-mediated cell-cell and cell-extracellular matrix (ECM) attachments. Kindlin-3 is expressed in hematopoietic cells, platelets, and endothelial cells. Studies have shown that kindlin-3 stabilizes cell adhesion mediated by ß1, ß2, and ß3 integrins. Apart from integrin cytoplasmic tails, kindlins are known to interact with other cytoplasmic proteins. Here we demonstrate that kindlin-3 can associate with ribosome via the receptor for activated-C kinase 1 (RACK1) scaffold protein based on immunoprecipitation, ribosome binding, and proximity ligation assays. We show that kindlin-3 regulates c-Myc protein expression in the human chronic myeloid leukemia cell line K562. Cell proliferation was reduced following siRNA reduction of kindlin-3 expression and a significant reduction in tumor mass was observed in xenograft experiments. Mechanistically, kindlin-3 is involved in integrin α5ß1-Akt-mTOR-p70S6K signaling; however, its regulation of c-Myc protein expression could be independent of this signaling axis.
踝蛋白是含有FERM结构域的细胞质蛋白，可调节整合素介导的细胞间和细胞与细胞外基质（ECM）的附着。踝蛋白-3在造血细胞、血小板和内皮细胞中表达。研究表明，踝蛋白-3可稳定由β1、β2和β3整合素介导的细胞黏附。除了整合素细胞质尾巴外，已知踝蛋白还可与其他细胞质蛋白相互作用。在此，我们通过免疫沉淀、核糖体结合和邻近连接分析证明，踝蛋白-3可通过活化C激酶1（RACK1）支架蛋白与核糖体结合。我们发现踝蛋白-3可调节人慢性髓性白血病细胞系K562中的c-Myc蛋白表达。在敲低踝蛋白-3表达的siRNA处理后，细胞增殖减少，并且在异种移植实验中观察到肿瘤块显著减小。从机制上讲，踝蛋白-3参与整合素α5β1-Akt-mTOR-p70S6K信号传导；然而，其对c-Myc蛋白表达的调节可能独立于该信号轴。
