Barnes Christopher J, Vadlamudi Ratna K, Mishra Sandip K, Jacobson Raymond H, Li Feng, Kumar Rakesh
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Nat Struct Biol. 2003 Aug;10(8):622-8. doi: 10.1038/nsb957.
The C-terminal binding protein 1 (CtBP) is a ubiquitous corepressor linking the recruitment of DNA- and histone-modifying proteins to sequence-specific DNA-binding proteins and facilitating gene regulation during development and oncogenesis. We describe here the binding, phosphorylation and functional regulation of CtBP by the p21-activated kinase 1 (Pak1). Pak1 phosphorylates CtBP selectively on Ser158 within a putative regulatory loop, triggering CtBP cellular redistribution and blocking CtBP corepressor functions. A S158A substitution in CtBP or Pak1 knockdown by short interference RNA blocked CtBP phosphorylation, redistribution and attenuation of CtBP corepressor functions in reporter and chromatin assays. In the presence of NADH, Pak1 superphosphorylates CtBP and inhibits CtBP dehydrogenase activity, suggesting that preferential phosphorylation of active CtBP may alter secondary structures and influence both enzymatic and corepressor functions. Pak1 regulation of CtBP represents a new model of corepressor regulation whereby cellular signaling cascades may influence gene expression in mammalian cells.
C 末端结合蛋白 1（CtBP）是一种普遍存在的共抑制因子，它将 DNA 和组蛋白修饰蛋白的募集与序列特异性 DNA 结合蛋白联系起来，并在发育和肿瘤发生过程中促进基因调控。我们在此描述 p21 激活激酶 1（Pak1）对 CtBP 的结合、磷酸化及功能调控。Pak1 在一个假定的调控环内选择性地将 CtBP 的丝氨酸 158 磷酸化，触发 CtBP 的细胞内重新分布并阻断 CtBP 的共抑制因子功能。在报告基因和染色质分析中，CtBP 中的 S158A 替代或通过短干扰 RNA 敲低 Pak1 可阻断 CtBP 的磷酸化、重新分布以及 CtBP 共抑制因子功能的减弱。在烟酰胺腺嘌呤二核苷酸（NADH）存在的情况下，Pak1 使 CtBP 过度磷酸化并抑制 CtBP 脱氢酶活性，这表明活性 CtBP 的优先磷酸化可能会改变二级结构并影响酶活性和共抑制因子功能。Pak1 对 CtBP 的调控代表了一种新的共抑制因子调控模型，即细胞信号级联反应可能会影响哺乳动物细胞中的基因表达。
