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EMBO Rep. 2014 Sep;15(9):938-47. doi: 10.15252/embr.201438808. Epub 2014 Jul 23.

Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2.

Author information

1
UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
2
Department of Chemistry, University of Wisconsin, Madison, WI, USA.
3
Department of Chemistry, University of Wisconsin, Madison, WI, USA University of Wisconsin School of Pharmacy, Madison, WI, USA.
4
UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA ehbresni@wisc.edu.

Abstract

Disease mutations provide unique opportunities to decipher protein and cell function. Mutations in the master regulator of hematopoiesis GATA-2 underlie an immunodeficiency associated with myelodysplastic syndrome and leukemia. We discovered that a GATA-2 disease mutant (T354M) defective in chromatin binding was hyperphosphorylated by p38 mitogen-activated protein kinase. p38 also induced multisite phosphorylation of wild-type GATA-2, which required a single phosphorylated residue (S192). Phosphorylation of GATA-2, but not T354M, stimulated target gene expression. While crosstalk between oncogenic Ras and GATA-2 has been implicated as an important axis in cancer biology, its mechanistic underpinnings are unclear. Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity.

KEYWORDS:

GATA factor; GATA‐2; Ras; p38; transcription

PMID:
25056917
PMCID:
PMC4198037
DOI:
10.15252/embr.201438808
[Indexed for MEDLINE]
Free PMC Article

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