title: Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2.
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.
authors: 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.
authors: Koichi R
authors: KR
authors: Katsumura
authors: Department of Chemistry, University of Wisconsin, Madison, WI, USA.
authors: Chenxi
authors: C
authors: Yang
authors: 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.
authors: Meghan E
authors: ME
authors: Boyer
authors: Department of Chemistry, University of Wisconsin, Madison, WI, USA University of Wisconsin School of Pharmacy, Madison, WI, USA.
authors: Lingjun
authors: L
authors: Li
authors: 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.
authors: Emery H
authors: EH
authors: Bresnick
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009190:Myelodysplastic Syndromes; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002843:Chromatin; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases
keywords: GATA factor; GATA‐2; Ras; p38; transcription