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1.
Oncogene ; 28(38): 3349-59, 2009 Sep 24.
Article in English | MEDLINE | ID: mdl-19581930

ABSTRACT

Leukemogenesis requires two classes of mutations, one that promotes proliferation and one that blocks differentiation. The erythroleukemia induced by Friend virus is a multistage disease characterized by an early proliferative stage driven by the interaction of the viral glycoprotein, gp55, with Sf-Stk and the EpoR, and a late block to differentiation resulting from retroviral insertion in the Pu.1 locus. We demonstrate here that activation of Stat3 by Sf-Stk in the early stage of disease is essential for the progression of erythroleukemia in the presence of differentiation signals induced by the EpoR, but is dispensable in the late stages of the disease. Furthermore, we identify Pu.1 as a Stat3 target gene in the early stages of erythroleukemia development. Our results support a model whereby the activation of Stat3 in the early stage of disease plays a pivotal role in regulating differentiation through the upregulation of Pu.1, thus inhibiting differentiation and favoring the expansion of infected erythroblasts and enhancing the pool of progenitors available for the acquisition of additional mutations, including insertional activation of Pu.1, resulting in full leukemic transformation.


Subject(s)
Erythroblasts/cytology , Gene Expression Regulation , Leukemia, Erythroblastic, Acute/etiology , Proto-Oncogene Proteins/genetics , STAT3 Transcription Factor/physiology , Trans-Activators/genetics , Adaptor Proteins, Signal Transducing , Animals , Cell Differentiation , Friend murine leukemia virus , Mice , Mice, Inbred BALB C , Phosphoproteins/physiology
2.
Oncogene ; 25(17): 2433-43, 2006 Apr 20.
Article in English | MEDLINE | ID: mdl-16314834

ABSTRACT

Friend virus induces the development of erythroleukemia in mice through the interaction of a viral glycoprotein, gp55, with a truncated form of the Stk receptor tyrosine kinase, short form-Stk (Sf-Stk), and the EpoR. We have shown previously that the ability of Sf-Stk to participate in the transformation of Friend virus-infected cells requires the kinase activity and Grb2-binding site of Sf-Stk. Here we show that Grb2 heterozygous mice exhibit decreased susceptibility to Friend erythroleukemia and that expansion of erythroid progenitors in response to infection requires the C-terminal SH3 domain of Grb2. A fusion protein in which the Grb2-binding site in Sf-Stk is replaced by Gab2, supports the growth of progenitors from mice lacking Sf-Stk, whereas a Sf-Stk/Gab1 fusion protein does not. Gab2 is expressed in spleens from Friend virus-infected mice, co-immunoprecipitates with Sf-Stk and is tyrosine phosphorylated in the presence of Sf-Stk. Mice with a targeted deletion in Gab2 are less susceptible to Friend erythroleukemia and the expansion of erythroid progenitor cells in response to infection can be rescued by expression of Gab2, but not Gab1. Taken together, these data indicate that a Sf-Stk/Grb2/Gab2 complex mediates the growth of primary erythroid progenitor cells in response to Friend virus.


Subject(s)
Friend murine leukemia virus/pathogenicity , GRB2 Adaptor Protein/physiology , Phosphoproteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Adaptor Proteins, Signal Transducing , Animals , Erythroid Precursor Cells/metabolism , Erythroid Precursor Cells/virology , Female , GRB2 Adaptor Protein/genetics , Immunoprecipitation , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Phosphoproteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Signal Transduction , src Homology Domains
3.
Nat Genet ; 23(2): 159-65, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10508511

ABSTRACT

The Friend virus susceptibility 2 (Fv2) locus encodes a dominant host factor that confers susceptibility to Friend virus-induced erythroleukaemia in mice. We mapped Fv2 to a 1.0-Mb interval that also contained the gene (Ron) encoding the stem cell kinase receptor (Stk). A truncated form of Stk (Sf-stk), which was the most abundant form of Stk in Fv2-sensitive (Fv2ss) erythroid cells, was not expressed in Fv2 resistant (Fv2rr) cells. Enforced expression of Sf-stk conferred susceptibility to Friend disease, whereas targeted disruption of Ron caused resistance. We conclude that the Fv2 locus encodes Ron, and that a naturally expressed, truncated form of Stk confers susceptibility to Friend virus-induced erythroleukaemia.


Subject(s)
Friend murine leukemia virus , Leukemia, Erythroblastic, Acute/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Cell Surface/genetics , 3T3 Cells , Animals , Base Sequence , Chromosome Mapping , Cloning, Molecular , Contig Mapping , Gene Expression , Genetic Predisposition to Disease , Mice , Mice, Inbred AKR , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred CBA , Mice, Inbred NZB , Mice, Inbred Strains , Molecular Sequence Data , Muridae , Protein Isoforms/genetics , Retroviridae Infections/genetics , Species Specificity , Spleen/cytology , Spleen/metabolism , Spleen/pathology , Tumor Virus Infections/genetics
5.
Nat Genet ; 13(3): 309-15, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8673130

ABSTRACT

Protein tyrosine phosphorylation plays a key role in regulating eukaryotic cell proliferation and differentiation. Genetic analysis in invertebrates has been invaluable for dissecting the signalling events downstream of receptor tyrosine kinases (RTKs). We have used this approach in mammals to analyse the interactions between the Kit RTK encoded by the murine Dominant white spotting (W) locus and the Shp1 protein tyrosine phosphatase, the product of the murine motheaten (me) gene. Homozygosity for mutations in both W and me ameliorates aspects of both the me and W phenotypes, including the lethal lung disease associated with me and the embryonic lethality and mast cell deficiency associated with W, demonstrating that the Kit receptor plays a role in the pathology of the me phenotype and conversely that Shp1 negatively regulates Kit signalling in vivo.


Subject(s)
Mutation , Protein Tyrosine Phosphatases/metabolism , Proto-Oncogene Proteins c-kit/genetics , Signal Transduction , Anemia/genetics , Animals , Autoimmune Diseases/genetics , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Gene Expression Regulation , Genes, Lethal , Genetic Complementation Test , Homozygote , Intracellular Signaling Peptides and Proteins , Lung Diseases/genetics , Mast Cells/pathology , Mast Cells/physiology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Mutant Strains , Models, Biological , Phenotype , Piebaldism/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 6 , Proto-Oncogene Proteins c-kit/metabolism
6.
Semin Immunol ; 7(4): 267-77, 1995 Aug.
Article in English | MEDLINE | ID: mdl-8520031

ABSTRACT

The ongoing production of mature blood cells during the lifetime of an animal is vital for survival. Hematopoiesis is the complex process whereby a small population of pluripotential stem cells give rise to mature cell types with specialized functions. The development of mature blood cells proceeds in a hierarchical fashion originating from a self-renewable stem cell population that gradually becomes committed to lineage-restricted differentiation. Two major themes concerning the regulation of hematopoiesis have emerged. First, the proliferation, survival and differentiation of immature progenitor cells depends on extracellular signals produced by cells within the hematopoietic microenvironment. Second, protein tyrosine phosphorylation is the major biochemical mechanism by which the extracellular signals are transmitted and interpreted. In this review we will concentrate on the role of receptors with intrinsic tyrosine kinase activity (RTKs) in hematopoietic regulation. RTKs form part of a highly conserved signaling mechanism that plays an important role in the development of evolutionary diverse organisms. During hematopoiesis, RTKs are a central component of the mechanism by which hematopoietic stem cells receive extracellular signals and interpret these signals to direct the lineage restricted differentiation of multipotential progenitors. In addition, RTKs may also play an important regulatory role in the ontogeny of the hematopoietic system during embryonic and fetal development. Taken together, RTKs are an important component of the mechanisms that regulate the development and behavior of hematopoietic stem cells.


Subject(s)
Hematopoiesis , Hematopoietic Stem Cells/enzymology , Receptor Protein-Tyrosine Kinases/physiology , Animals
7.
Mol Cell Biol ; 11(1): 226-39, 1991 Jan.
Article in English | MEDLINE | ID: mdl-1898762

ABSTRACT

The proto-oncogene fps/fes encodes a distinctive type of protein-tyrosine kinase. We identified a Drosophila gene (dfps85D) whose product resembles the proteins encoded by vertebrate fps/fes and the closely related gene fer. dfps85D is located at chromosomal position 85D10-13 and is unlikely to correspond to any previously defined genetic locus in Drosophila melanogaster. Expression of the gene is entirely zygotic in origin and occurs throughout the life cycle. But hybridization in situ revealed that the pattern of expression is specialized and evolves in a provocative manner. The most notable feature of expression is the diversity of developmental periods, tissues, and cells in which it occurs. In some tissues, expression is transient; in others, it is continuous. Expression occurs in both mitotic and terminally differentiated tissue and, at various times in development, is prominent in imaginal disks, gut, muscle, testes, ovaries, retina, and other neural tissues. It appears that the use of dfps85D is more diversified than that of other Drosophila protein-tyrosine kinases reported to date and contrasts sharply with the restricted expression of fps itself in vertebrates. The detailed description of expression provided here will help guide the search for mutants in dfps85D.


Subject(s)
Drosophila melanogaster/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Amino Acid Sequence , Animals , Base Sequence , Chromosome Mapping , Cloning, Molecular , Drosophila melanogaster/growth & development , Gene Expression , Genes , Molecular Sequence Data , Nucleic Acid Hybridization , RNA, Messenger/genetics , Restriction Mapping , Tissue Distribution
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