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3.
Curr Opin Hematol ; 8(4): 206-11, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11561157

ABSTRACT

Translocations involving a variety of fusion partners, such as promyelocytic leukemia gene, promyelocytic leukemia zinc finger, nucleophosmin, nuclear matrix protein, and signal transducer and activator of transcription protein 5B, with the retinoic acid receptor alpha gene are commonly associated with development of acute promyelocytic leukemia. Through the development of transgenic mouse models, some retinoic acid receptor alpha translocation fusion proteins have been shown to be capable of initiating acute promyelocytic leukemia development, and dictate the leukemias' responsiveness to retinoic acid. Transgenic mouse models also have identified the influence of reciprocal translocation fusion proteins on acute promyelocytic leukemia development, and have demonstrated that additional mutations can contribute to the development of acute promyelocytic leukemia. In this review, the authors summarize current mouse models of acute promyelocytic leukemia and describe current knowledge about additional genetic alterations that occur during development of acute promyelocytic leukemia in the mouse.


Subject(s)
Disease Models, Animal , Leukemia, Promyelocytic, Acute/genetics , Animals , Antineoplastic Agents/therapeutic use , Arsenic/therapeutic use , Chromosome Deletion , Leukemia, Promyelocytic, Acute/drug therapy , Mice , Models, Biological , Mutation , Neoplasm Proteins/physiology , Oncogene Proteins, Fusion/physiology , Tretinoin/therapeutic use
4.
EMBO J ; 18(8): 2165-73, 1999 Apr 15.
Article in English | MEDLINE | ID: mdl-10205170

ABSTRACT

Receptors of the Eph family and their ligands (ephrins) mediate developmental vascular assembly and direct axonal guidance. Migrating cell processes identify appropriate targets within migratory fields based on topographically displayed ephrin gradients. Here, EphB1 regulated cell attachment by discriminating the density at which ephrin-B1 was displayed on a reconstituted surface. EphB1-ephrin-B1 engagement did not promote cell attachment through mechanical tethering, but did activate integrin-mediated attachment. In endothelial cells, attachment to RGD peptides or fibrinogen was mediated through alphavbeta3 integrin. EphB1 transfection conferred ephrin-B1-responsive activation of alpha5beta1 integrin-mediated cell attachment in human embryonic kidney cells. Activation-competent but signaling-defective EphB1 point mutants failed to stimulate ephrin-B1 dependent attachment. These findings lead us to propose that EphB1 functions as a 'ligand density sensor' to signal integrin-mediated cell-matrix attachment.


Subject(s)
Cell Adhesion , Membrane Proteins/metabolism , Receptors, Fibronectin/metabolism , Receptors, Vitronectin/metabolism , Cell Line , Ephrin-B1 , Humans , Signal Transduction , Surface Properties
5.
Genes Dev ; 12(5): 667-78, 1998 Mar 01.
Article in English | MEDLINE | ID: mdl-9499402

ABSTRACT

Eph family receptor tyrosine kinases (including EphA3, EphB4) direct pathfinding of neurons within migratory fields of cells expressing gradients of their membrane-bound ligands. Others (EphB1 and EphA2) direct vascular network assembly, affecting endothelial migration, capillary morphogenesis, and angiogenesis. To explore how ephrins could provide positional labels for cell targeting, we tested whether endogenous endothelial and P19 cell EphB1 (ELK) and EphB2 (Nuk) receptors discriminate between different oligomeric forms of an ephrin-B1/Fc fusion ligand. Receptor tyrosine phosphorylation was stimulated by both dimeric and clustered multimeric ephrin-B1, yet only ephrin-B1 multimers (tetramers) promoted endothelial capillary-like assembly, cell attachment, and the recruitment of low-molecular-weight phosphotyrosine phosphatase (LMW-PTP) to receptor complexes. Cell-cell contact among cells expressing both EphB1 and ephrin-B1 was required for EphB1 activation and recruitment of LMW-PTP to EphB1 complexes. The EphB1-binding site for LMW-PTP was mapped and shown to be required for tetrameric ephrin-B1 to recruit LMW-PTP and to promote attachment. Thus, distinct EphB1-signaling complexes are assembled and different cellular attachment responses are determined by a receptor switch mechanism responsive to distinct ephrin-B1 oligomers.


Subject(s)
Membrane Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Animals , Cell Adhesion , Cells, Cultured , Dimerization , Endothelium, Vascular/cytology , Ephrin-B1 , Fibronectins/metabolism , Immunoglobulin Fc Fragments/genetics , Immunoglobulin Fc Fragments/metabolism , Membrane Proteins/chemistry , Membrane Proteins/genetics , Mice , Molecular Weight , Mutation , Phosphorylation , Protein Tyrosine Phosphatases/chemistry , Protein Tyrosine Phosphatases/metabolism , Receptor Protein-Tyrosine Kinases/chemistry , Receptor, EphB2 , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Teratocarcinoma/metabolism , Tyrosine/metabolism
6.
J Biol Chem ; 273(3): 1303-8, 1998 Jan 16.
Article in English | MEDLINE | ID: mdl-9430661

ABSTRACT

Eph family receptor tyrosine kinases signal axonal guidance, neuronal bundling, and angiogenesis; yet the signaling systems that couple these receptors to targeting and cell-cell assembly responses are incompletely defined. Functional links to regulators of cytoskeletal structure are anticipated based on receptor mediated cell-cell aggregation and migratory responses. We used two-hybrid interaction cloning to identify EphB1-interactive proteins. Six independent cDNAs encoding the SH2 domain of the adapter protein, Nck, were recovered in a screen of a murine embryonic library. We mapped the EphB1 subdomain that binds Nck and its Drosophila homologue, DOCK, to the juxtamembrane region. Within this subdomain, Tyr594 was required for Nck binding. In P19 embryonal carcinoma cells, activation of EphB1 (ELK) by its ligand, ephrin-B1/Fc, recruited Nck to native receptor complexes and activated c-Jun kinase (JNK/SAPK). Transient overexpression of mutant EphB1 receptors (Y594F) blocked Nck recruitment to EphB1, attenuated downstream JNK activation, and blocked cell attachment responses. These findings identify Nck as an important intermediary linking EphB1 signaling to JNK.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Membrane Proteins/metabolism , Mitogen-Activated Protein Kinases , Oncogene Proteins/metabolism , Adaptor Proteins, Signal Transducing , Animals , COS Cells , Cell Adhesion , Drosophila Proteins , Enzyme Activation , Ephrin-B1 , Fibronectins/metabolism , Humans , JNK Mitogen-Activated Protein Kinases , Ligands , Membrane Proteins/genetics , Mutagenesis, Site-Directed , Nerve Tissue Proteins/metabolism , Transfection , Tyrosine/metabolism
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