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Related Collections Hematopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 92 No. 6 (September 15), 1998: pp. 1989-2002 Saturation Mutagenesis of the  Subunit of the Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor Shows Clustering of Constitutive Mutations, Activation of ERK MAP Kinase and STAT Pathways, and Differential  Subunit Tyrosine Phosphorylation Brendan J. Jenkins, Timothy J. Blake, and Thomas J. Gonda From the Hanson Centre for Cancer Research and Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia. The high-affinity receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are heterodimeric complexes consisting of cytokine-specific subunits and a common signal-transducing  subunit (hc). We have previously demonstrated the oncogenic potential of this group of receptors by identifying constitutively activating point mutations in the extracellular and transmembrane domains of hc. We report here a comprehensive screen of the entire hc molecule that has led to the identification of additional constitutive point mutations by virtue of their ability to confer factor independence on murine FDC-P1 cells. These mutations were clustered exclusively in a central region of hc that encompasses the extracellular membrane-proximal domain, transmembrane domain, and membrane-proximal region of the cytoplasmic domain. Interestingly, most hc mutants exhibited cell type-specific constitutive activity, with only two transmembrane domain mutants able to confer factor independence on both murine FDC-P1 and BAF-B03 cells. Examination of the biochemical properties of these mutants in FDC-P1 cells indicated that MAP kinase (ERK1/2), STAT, and JAK2 signaling molecules were constitutively activated. In contrast, only some of the mutant  subunits were constitutively tyrosine phosphorylated. Taken together, these results highlight key regions involved in hc activation, dissociate hc tyrosine phosphorylation from MAP kinase and STAT activation, and suggest the involvement of distinct mechanisms by which proliferative signals can be generated by hc. © 1998 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. L. Brown, C. R. Wilkinson, S. R. Waterman, C. H. Kok, D. G. Salerno, S. M. Diakiw, B. Reynolds, H. S. Scott, A. Tsykin, G. F. Glonek, et al. Genetic regulators of myelopoiesis and leukemic signaling identified by gene profiling and linear modeling J. Leukoc. Biol., August 1, 2006; 80(2): 433 - 447. [Abstract] [Full Text] [PDF] A. L. Brown, M. Peters, R. J. D'Andrea, and T. J. Gonda Constitutive mutants of the GM-CSF receptor reveal multiple pathways leading to myeloid cell survival, proliferation, and granulocyte-macrophage differentiation Blood, January 15, 2004; 103(2): 507 - 516. [Abstract] [Full Text] [PDF] V. T. Phan, D. B. Shultz, B.-T. H. Truong, T. J. Blake, A. L. Brown, T. J. Gonda, M. M. Le Beau, and S. C. Kogan Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation Mol. Cell. Biol., July 1, 2003; 23(13): 4573 - 4585. [Abstract] [Full Text] [PDF] T. J. Blake, B. J. Jenkins, R. J. D'Andrea, and T. J. Gonda Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the {beta}-subunit of the GM-CSF receptor J. Leukoc. Biol., December 1, 2002; 72(6): 1246 - 1255. [Abstract] [Full Text] [PDF] F. Le, F. Stomski, J. M. Woodcock, A. F. Lopez, and T. J. Gonda The Role of Disulfide-linked Dimerization in Interleukin-3 Receptor Signaling and Biological Activity J. Biol. Chem., February 18, 2000; 275(7): 5124 - 5130. [Abstract] [Full Text] [PDF] M. P. McCormack and T. J. Gonda Novel murine myeloid cell lines that exhibit a differentiation switch in response to IL-3 or GM-CSF, or to different constitutively active mutants of the GM-CSF receptor beta subunit Blood, January 1, 2000; 95(1): 120 - 127. [Abstract] [Full Text] [PDF] K. E. Borg, M. Zhang, D. Hegge, R. L. Stephen, D. J. Buckley, N. S. Magnuson, and A. R. Buckley Prolactin Regulation of pim-1 Expression: Positive and Negative Promoter Elements Endocrinology, December 1, 1999; 140(12): 5659 - 5668. [Abstract] [Full Text] B. J. Jenkins, F. Le, and T. J. Gonda A Cell Type-specific Constitutive Point Mutant of the Common beta -Subunit of the Human Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF), Interleukin (IL)-3, and IL-5 Receptors Requires the GM-CSF Receptor alpha -Subunit for Activation J. Biol. Chem., March 26, 1999; 274(13): 8669 - 8677. [Abstract] [Full Text] [PDF] H. Sakamoto, T. Kitamura, and A. Yoshimura Mitogen-activated Protein Kinase Plays an Essential Role in the Erythropoietin-dependent Proliferation of CTLL-2 Cells J. Biol. Chem., November 10, 2000; 275(46): 35857 - 35862. [Abstract] [Full Text] [PDF]

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