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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros
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Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros

机译：SYK丝氨酸磷酸化对Ikaros的核定位和转录因子功能至关重要

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摘要

Ikaros is a zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis through transcriptional regulation of the earliest stages of lymphocyte ontogeny and differentiation. Functional deficiency of Ikaros has been implicated in the pathogenesis of acute lymphoblastic leukemia, the most common form of childhood cancer. Therefore, a stringent regulation of Ikaros activity is considered of paramount importance, but the operative molecular mechanisms responsible for its regulation remain largely unknown. Here we provide multifaceted genetic and biochemical evidence for a previously unknown function of spleen tyrosine kinase (SYK) as a partner and posttranslational regulator of Ikaros. We demonstrate that SYK phoshorylates Ikaros at unique C-terminal serine phosphorylation sites S358 and S361, thereby augmenting its nuclear localization and sequence-specific DNA binding activity. Mechanistically, we establish that SYK-in-duced Ikaros activation is essential for its nuclear localization and optimal transcription factor function.
机译：伊卡罗斯（Ikaros）是一种含锌指的DNA结合蛋白，通过对淋巴细胞发生和分化的最早阶段进行转录调控，在免疫稳态中发挥关键作用。 Ikaros的功能缺陷与急性淋巴细胞白血病（儿童期最常见的癌症）的发病机理有关。因此，严格规定Ikaros活性至关重要，但对其调节起作用的分子机制在很大程度上尚不清楚。在这里，我们提供了脾酪氨酸激酶（SYK）作为Ikaros的伴侣和翻译后调节剂以前未知功能的多方面遗传和生物化学证据。我们证明，SYK在独特的C端丝氨酸磷酸化位点S358和S361磷酸Ikaros，从而增加其核定位和序列特异性DNA结合活性。从机理上讲，我们确定SYK诱导的Ikaros激活对其核定位和最佳转录因子功能至关重要。

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    Fatih M. Uckun; Hong Ma; Jian Zhang; Zahide Ozer; Sinisa Dovat; Cheney Mao; Rita Ishkhanian; Patricia Goodman; Sanjive Qazi;

  • 作者单位

    Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027,Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA 90027;

    Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027,Departments of Biochemistry and Molecular Biology, Molecular Oncology Program, Parker Hughes Institute, St. Paul, MN 55113;

    Department of Pathophysiology, Medicinal Bioinformatics Center, Shanghai Jiaotong University School of Medicine, Shanghai, China;

    Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027,Departments of Biochemistry and Molecular Biology, Molecular Oncology Program, Parker Hughes Institute, St. Paul, MN 55113;

    Department of Pediatrics, Division of Pediatric Hematology/ Oncology, College of Medicine, Pennsylvania State University, Hershey, PA 17033;

    Department of Structural Biology, Viva Biotech, Chicago, IL 60612;

    Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027;

    Departments of Biochemistry and Molecular Biology, Molecular Oncology Program, Parker Hughes Institute, St. Paul, MN 55113,Department of Veterinary and Biomedical Science, University of Minnesota, St. Paul, MN 55108;

    Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027,Department of Biology and Bioinformatics Program, Gustavus Adolphus College, St. Peter, MN 56082;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    systems immunobiology; bioinformatics; site-directed mutagenesis; signaling; molecular modeling;

    机译：系统免疫生物学;生物信息学定点诱变;发信号分子模拟;

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