Takakura Yuki, Yamaguchi Noritaka, Honda Takuya, Morii Mariko, Yuki Ryuzaburo, Nakayama Yuji, Yamaguchi Naoto
Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University.
Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University.
Biol Pharm Bull. 2017;40(11):1968-1975. doi: 10.1248/bpb.b17-00548.
Anaplastic lymphoma kinase (ALK) is a receptor-type tyrosine kinase that promotes cell growth upon stimulation with ligands such as midkine and pleiotrophin. Recently, a truncated isoform of ALK was identified in a variety of tumors. This isoform is expressed from a novel ALK transcript initiated from a de novo alternative transcription initiation (ATI) site in ALK intron 19 (referred to as ALK). ALK, which consists of only the intracellular kinase domain, localizes to the nucleus as well as the cytoplasm. However, its nuclear role is unknown. In this study, we determined that ALK promoted chromatin structural changes in the nucleus in a kinase activity-dependent manner. We found that expression of ALK increased the level of the heterochromatin marker Lys9 tri-methylated histone H3. In addition, we demonstrated that ALK phosphorylated the nuclear protein A-kinase anchoring protein 8 (AKAP8) and altered its subcellular localization from the insoluble fraction to the soluble fraction. These results suggest that ALK induces chromatin structural changes and heterochromatinization through phosphorylation of AKAP8 in the nucleus.
间变性淋巴瘤激酶（ALK）是一种受体型酪氨酸激酶，在受到诸如中期因子和多效生长因子等配体刺激后可促进细胞生长。最近，在多种肿瘤中发现了ALK的一种截短异构体。这种异构体由一种新的ALK转录本表达而来，该转录本起始于ALK内含子19中的一个从头选择性转录起始（ATI）位点（称为ALK）。ALK仅由细胞内激酶结构域组成，定位于细胞核和细胞质中。然而，其在细胞核中的作用尚不清楚。在本研究中，我们确定ALK以激酶活性依赖的方式促进细胞核中的染色质结构变化。我们发现ALK的表达增加了异染色质标记物H3赖氨酸9三甲基化的水平。此外，我们证明ALK使核蛋白A激酶锚定蛋白8（AKAP8）磷酸化，并改变其亚细胞定位，从不溶性部分转移到可溶性部分。这些结果表明，ALK通过在细胞核中使AKAP8磷酸化来诱导染色质结构变化和异染色质化。
