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PMID:23071339

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Citation

Uckun, FM, Ma, H, Zhang, J, Ozer, Z, Dovat, S, Mao, C, Ishkhanian, R, Goodman, P and Qazi, S (2012) Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros. Proc. Natl. Acad. Sci. U.S.A. 109:18072-7

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.

Links

PubMed PMC3497833 Online version:10.1073/pnas.1209828109

Keywords

Cell Nucleus/enzymology; Cell Nucleus/metabolism; Humans; Ikaros Transcription Factor/genetics; Ikaros Transcription Factor/metabolism; Intracellular Signaling Peptides and Proteins/metabolism; Mutagenesis, Site-Directed; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism; Protein-Tyrosine Kinases/metabolism; Serine/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CD19

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CD19

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P15391

C

Seeded From UniProt

complete

HUMAN:KSYK

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KSYK

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KSYK

acts_upstream_of_or_within

GO:0006606: protein import into nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KSYK

acts_upstream_of_or_within

GO:0051090: regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KSYK

located_in

GO:0005634: nucleus

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

C

Seeded From UniProt

complete

MOUSE:KSYK

located_in

GO:0005737: cytoplasm

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

C

Seeded From UniProt

complete

MOUSE:IKZF1

acts_upstream_of_or_within

GO:0030183: B cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IKZF1

acts_upstream_of_or_within

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IKZF1

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:IKZF1

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13422

C

Seeded From UniProt

complete

HUMAN:KSYK

involved_in

GO:0051090: regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KSYK

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KSYK

involved_in

GO:0006606: protein import into nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KSYK

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KSYK

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KSYK

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:KSYK

part_of

GO:0005634: nucleus

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

C

Seeded From UniProt

complete

MOUSE:KSYK

part_of

GO:0005737: cytoplasm

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

C

Seeded From UniProt

complete

MOUSE:KSYK

acts_upstream_of_or_within

GO:0006606: protein import into nucleus

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

P

Seeded From UniProt

complete

MOUSE:KSYK

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

F

Seeded From UniProt

complete

MOUSE:KSYK

GO:1900180: regulation of protein localization to nucleus

ECO:0000314:

P

Figure 3 shows Wild Type vs. Mutant IK (Ikaros)proteins. In contrast to wild-type IK, SYK-resistant IK protein M1-1 carrying A-mutations at both SYK phosphorylation sites showed no detectable nuclear localization when overexpressed in 293T cells

complete
CACAO 7847

MOUSE:KSYK

acts_upstream_of_or_within

GO:0018105: peptidyl-serine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KSYK

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

C

Seeded From UniProt

complete

MOUSE:KSYK

acts_upstream_of_or_within

GO:0051090: regulation of DNA-binding transcription factor activity

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P43405

P

Seeded From UniProt

complete

HUMAN:IKZF1

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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