POINT MUTATIONS WITHIN A DIMER INTERFACE HOMOLOGY DOMAIN OF C-MPL INDUCE CONSTITUTIVE RECEPTOR ACTIVITY AND TUMORIGENICITY
- Author(s)
- Alexander, WS; Metcalf, D; Dunn, AR;
- Details
- Publication Year 1995-11-15,Volume 14,Issue #22,Page 5569-5578
- Journal Title
- EMBO JOURNAL
- Publication Type
- Journal Article
- Abstract
- c-Mpl, a receptor for thrombopoietin (TPO), belongs to the haemopoietin/cytokine receptor superfamily, a group of cell surface molecules characterized by conserved sequence motifs within their ligand binding domains, A recurring mechanism for the activation of haemopoietin receptors is the formation of functional complexes by receptor subunit oligomerization, Within the growth hormone receptor, a cluster of extracellular amino acids forms a dimer interface domain that stabilizes ligand-induced homodimers. This domain appears to be functionally conserved in the erythropoietin (EPO) receptor because substitution of cysteines for residues in the analogous region causes EPO-independent receptor activation via disulfide-linked homodimerization. This report identifies an homologous domain within the c-Mpl receptor. The substitution of cysteine residues for specific amino acids in the dimer interface homology regions of c-Mpl induced constitutive receptor activity. Factor-dependent FDC-P1 and Ba/F3 cells expressing the active receptor mutants no longer required exogenous factors and proliferated autonomously. The results imply that the normal process of TPO-stimulated Mpl activation occurs through receptor homodimerization and is mediated by a conserved haemopoietin receptor dimer interface domain, Moreover, cells expressing activated mutant Mpl receptors were tumorigenic in transplanted mice, Thus, like v-mpl, its viral counterpart, mutated forms of the cellular mpl gene also have oncogenic potential.
- Publisher
- OXFORD UNIV PRESS UNITED KINGDOM
- Keywords
- COLONY-STIMULATING FACTOR; HUMAN GROWTH-HORMONE; IL-6 SIGNAL TRANSDUCER; EXTRACELLULAR DOMAIN; MOLECULAR-CLONING; ERYTHROPOIETIN RECEPTOR; PROLACTIN RECEPTOR; EXPRESSION; SUPERFAMILY; PROTOONCOGENE
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Creation Date: 1995-11-15 12:00:00