Regulatory Phosphorylation of Ikaros by Bruton's Tyrosine Kinase

• Published in: PloS one Vol. 8; no. 8; p. e71302
• Main Authors: Ma, Hong, Qazi, Sanjive, Ozer, Zahide, Zhang, Jian, Ishkhanian, Rita, Uckun, Fatih M.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.08.2013; Public Library of Science (PLoS)
• Subjects: Acute lymphoblastic leukemia; Agammaglobulinaemia Tyrosine Kinase; Animals; Apoptosis; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Bioinformatics; Biology; Biotechnology; Blood diseases; Bruton's tyrosine kinase; Cancer; Cell Line, Tumor; Cell Nucleus - genetics; Cell Nucleus - metabolism; Children; Children & youth; Cooperation; Deoxyribonucleic acid; DNA; DNA binding proteins; DNA-binding protein; Gene Expression Regulation, Leukemic; Genes; Homeostasis; Human subjects; Humans; Ikaros protein; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - metabolism; Infant; Kinases; Laboratories; Leukemia; Localization; Lymphatic leukemia; Lymphocytes; Lymphoma; Medical prognosis; Medicine; Mice; Nucleotide sequence; Ontogeny; Pathogenesis; Phenols (Class of compounds); Phosphorylation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Binding; Protein-tyrosine kinase; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; Signal Transduction; Transcription factors; Tyrosine; Young Adult; Zinc; Zinc finger proteins; Zinc Fingers; Los Angeles California; Minnesota; California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0071302

Diminished Ikaros function has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Therefore, a stringent regulation of Ikaros is of paramount importance for normal lymphocyte ontogeny. Here we provide genetic and biochemical evidence for a previously unknown function of Bruton's tyrosine kinase (BTK) as a partner and posttranslational regulator of Ikaros, a zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis. We demonstrate that BTK phosphorylates Ikaros at unique phosphorylation sites S214 and S215 in the close vicinity of its zinc finger 4 (ZF4) within the DNA binding domain, thereby augmenting its nuclear localization and sequence-specific DNA binding activity. Our results further demonstrate that BTK-induced activating phosphorylation is critical for the optimal transcription factor function of Ikaros.