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Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros.


ABSTRACT: 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-induced Ikaros activation is essential for its nuclear localization and optimal transcription factor function.

SUBMITTER: Uckun FM 

PROVIDER: S-EPMC3497833 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros.

Uckun Fatih M FM   Ma Hong H   Zhang Jian J   Ozer Zahide Z   Dovat Sinisa S   Mao Cheney C   Ishkhanian Rita R   Goodman Patricia P   Qazi Sanjive S  

Proceedings of the National Academy of Sciences of the United States of America 20121015 44


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 i  ...[more]

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