PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis.
The heterodimeric transcription factor RUNX1/PEBP2-beta (also known as AML1/CBF-beta) is essential for definitive hematopoiesis. Here, we show that interaction with PEBP2-beta leads to the phosphorylation of RUNX1, which in turn induces p300 phosphorylation. This is mediated by homeodomain interacting kinase 2 (HIPK2), targeting Ser(249), Ser(273), and Thr(276) in RUNX1, in a manner that is also dependent on the RUNX1 PY motif. Importantly, we observed the in vitro disruption of this phosphorylation cascade by multiple leukemogenic genetic defects targeting RUNX1/CBFB. In particular, the oncogenic protein PEBP2-beta-SMMHC prevents RUNX1/p300 phosphorylation by sequestering HIPK2 to mislocalized RUNX1/beta-SMMHC complexes. Therefore, phosphorylation of RUNX1 appears a critical step in its association with and phosphorylation of p300, and its disruption may be a common theme in RUNX1-associated leukemogenesis.
Wee
Hee-Jun
HJ
Genomics and Genetics Division, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Proteos, Singapore.
Voon
Dominic Chih-Cheng
DC
Bae
Suk-Chul
SC
Ito
Yoshiaki
Y
D000818:Animals; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000737:chemistry / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000378:metabolism*
C493692:CBFB protein, human; D023081:CCAAT-Binding Factor; D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D017931:DNA Primers; D046912:Multiprotein Complexes; C493728:RUNX1 protein, human; D011994:Recombinant Proteins; D050880:p300-CBP Transcription Factors; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases