The Truncated Isoform of the Receptor Tyrosine Kinase ALK Generated by Alternative Transcription Initiation (ALKATI) Induces Chromatin Structural Changes in the Nucleus in a Kinase Activity-Dependent Manner

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(ATI)). ALK(ATI), 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(ATI) promoted chromatin structural changes in the nucleus in a kinase activity-dependent manner. We found that expression of ALK(ATI) increased the level of the heterochromatin marker Lys9 tri-methylated histone 113. In addition, we demonstrated that ALK(ATI) 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(ATI) induces chromatin structural changes and heterochromatinization through phosphorylation of AKAP8 in the nucleus.