Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Science for Life Laboratory, Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
J Cell Biol. 2018 May 7;217(5):1701-1717. doi: 10.1083/jcb.201706118. Epub 2018 Mar 15.
Translocation of full-length or fragments of receptors to the nucleus has been reported for several tyrosine kinase receptors. In this paper, we show that a fraction of full-length cell surface platelet-derived growth factor (PDGF) receptor β (PDGFRβ) accumulates in the nucleus at the chromatin and the nuclear matrix after ligand stimulation. Nuclear translocation of PDGFRβ was dependent on PDGF-BB-induced receptor dimerization, clathrin-mediated endocytosis, β-importin, and intact Golgi, occurring in both normal and cancer cells. In the nucleus, PDGFRβ formed ligand-inducible complexes with the tyrosine kinase Fer and its substrate, TATA element-modifying factor 1 (TMF-1). PDGF-BB stimulation decreased TMF-1 binding to the transcriptional regulator Brahma-related gene 1 (Brg-1) and released Brg-1 from the SWI-SNF chromatin remodeling complex. Moreover, knockdown of TMF-1 by small interfering RNA decreased nuclear translocation of PDGFRβ and caused significant up-regulation of the Brg-1/p53-regulated cell cycle inhibitor (encoding p21) without affecting PDGFRβ-inducible immediate-early genes. In conclusion, nuclear interactions of PDGFRβ control proliferation by chromatin remodeling and regulation of p21 levels.
已有报道称，几种酪氨酸激酶受体的全长或受体片段可发生核转位。本文中，我们发现，配体刺激后，血小板衍生生长因子（PDGF）受体β（PDGFRβ）的全长细胞表面受体的一部分在染色质和核基质中积累到细胞核内。PDGFRβ 的核转位依赖于 PDGF-BB 诱导的受体二聚化、网格蛋白介导的内吞作用、β-importin 和完整的高尔基体，在正常细胞和癌细胞中均发生。在细胞核内，PDGFRβ 与 Fer 及其底物 TATA 元件修饰因子 1（TMF-1）形成配体诱导的复合物。PDGF-BB 刺激可降低 TMF-1 与转录调节因子 Brg-1 相关基因 1（Brahma-related gene 1，Brg-1）的结合，并将 Brg-1 从 SWI-SNF 染色质重塑复合物中释放出来。此外，通过小干扰 RNA 敲低 TMF-1 会减少 PDGFRβ 的核转位，并导致 Brg-1/p53 调节的细胞周期抑制剂（编码 p21）的显著上调，而不影响 PDGFRβ 诱导的即刻早期基因。综上所述，PDGFRβ 的核内相互作用通过染色质重塑和 p21 水平的调节来控制细胞增殖。
