Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros.
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.
Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Fatih M
FM
Uckun
Hong
H
Ma
Jian
J
Zhang
Zahide
Z
Ozer
Sinisa
S
Dovat
Cheney
C
Mao
Rita
R
Ishkhanian
Patricia
P
Goodman
Sanjive
S
Qazi
D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D000072377:Syk Kinase
D047908:Intracellular Signaling Peptides and Proteins; D051740:Ikaros Transcription Factor; D012694:Serine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase