Phosphatidylinositol 3′-Kinase and SH2-Containing Inositol Phosphatase (SHIP) Are Recruited by Distinct Positive and Negative Growth-Regulatory Domains in the Granulocyte Colony-Stimulating Factor Receptor

  • Hunter M
  • Avalos B
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Abstract

Activation of both positive and “negative” or anti-proliferative signals has emerged as a common paradigm for regulation of cell growth through cell surface receptors that regulate immune responses. SHP-1 and -2 and the novel 5′-inositol phosphatase SHIP have recently been shown to function as growth inhibitory molecules in immune receptor signaling. In the current study, we have identified distinct regions in the granulocyte colony-stimulating factor receptor (G-CSFR) distal to the conserved box 2 motif necessary for mitogenesis, which exert positive and negative influences on growth signaling in Ba/F3 pro-B lymphoid cells. The region spanning amino acids 682 to 715 mediates activation of phosphatidylinositol 3′(PI3)-kinase. Activation of PI3-kinase leads to inhibition of apoptosis, promotion of cell survival, and enhanced proliferative responses to G-CSF. We show that the region of 98 amino acids in the distal tail of the class I G-CSFR down-modulates proliferative signaling, not only in myeloid cell lines, as previously reported, but also in Ba/F3 cells. This same region recruits SHIP to the signaling cascade through a mechanism involving Shc, with the formation of Shc/SHIP complexes. Our data suggest a model in which PI3-kinase and SHIP coordinately regulate growth signaling through the G-CSFR.

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Hunter, M. G., & Avalos, B. R. (1998). Phosphatidylinositol 3′-Kinase and SH2-Containing Inositol Phosphatase (SHIP) Are Recruited by Distinct Positive and Negative Growth-Regulatory Domains in the Granulocyte Colony-Stimulating Factor Receptor. The Journal of Immunology, 160(10), 4979–4987. https://doi.org/10.4049/jimmunol.160.10.4979

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