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

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

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18072-18077
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number44
DOIs
StatePublished - Oct 30 2012

All Science Journal Classification (ASJC) codes

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