Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNAtranslation initiation inhibiting erythroid differentiation

The authors thank Dr Victor de Jager for assistance with the Rosetta Resolver software; Dr Ivo Touw for many fruitful discussions and critical reading of the manuscript; Liu Wing for technical assistance; Drs Peter Seither, Andreas Weith (Boehringer Ingelheim, Biberach, Germany), Helmuth Dolznig, Thomas Waerner, and Sandra Pilat (IMP, Vienna, Austria) for mRNA profiling of erythroblasts, of which the complete data will be published elsewhere; Dr Bart Aarts (Erasmus MC, Rotterdam, The Netherlands) for assistance in confocal scanning microscopy; Dr David Brautigan (University of Virginia, Charlottesville) for anti-Igbp1 antibodies; Dr Manfred Boehm (National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, MD) for anti-Uhmk1 antibodies; and Ortho-Biotech (Tilburg, The Netherlands) for their kind gift of Eprex (erythropoietin).Stem cell factor (SCF)–induced activation of phosphoinositide-3-kinase (PI3K) is required for transient amplification of the erythroblast compartment. PI3K stimulates the activation of mTOR (target of rapamycin) and subsequent release of the cap-binding translation initiation factor 4E (eIF4E) from the 4E-binding protein 4EBP, which controls the recruitment of structured mRNAs to polysomes. Enhanced expression of eIF4E renders proliferation of erythroblasts independent of PI3K. To investigate which mRNAs are selectively recruited to polysomes, we compared SCF-dependent gene expression between total and polysome-bound mRNA. This identified 111 genes primarily subject to translational regulation. For 8 of 9 genes studied in more detail, the SCF-induced polysome recruitment of transcripts exceeded 5-fold regulation and was PI3K-dependent and eIF4E-sensitive, whereas total mRNA was not affected by signal transduction. One of the targets, Immunoglobulin binding protein 1 (Igbp1), is a regulatory subunit of protein phosphatase 2A (Pp2a) sustaining mTOR signaling. Constitutive expression of Igbp1 impaired erythroid differentiation, maintained 4EBP and p70S6k phosphorylation, and enhanced polysome recruitment of multiple eIF4E-sensitive mRNAs. Thus, PI3K-dependent polysome recruitment of Igbp1 acts as a positive feedback mechanism on translation initiation underscoring the important regulatory role of selectivemRNArecruitment to polysomes in the balance between proliferation and maturation of erythroblasts. (Blood. 2008; 112:2750-2760)peer-reviewe

Igbpl is part of a positive feedback loop in stem cell factor-dependent, selective mRNA translation initiation inhibiting erythroid differentiation

Stem cell factor (SCF)-induced activation of phosphoinositide-3-kinase (PI3K) is required for transient amplification of the erythroblast compartment. PI3K stimulates the activation of mTOR (target of rapamycin) and subsequent release of the cap-binding translation initiation factor 4E (elF4E) from the 4E-binding protein 4EBP, which controls the recruitment of structured mRNAs to polysomes. Enhanced expression of elF4E renders proliferation of erythroblasts independent of PI3K. To investigate which mRNAs are selectively recruited to polysomes, we compared SCF-dependent gene expression between total and polysome-bound mRNA. This identified 111 genes primarily subject to translational regulation. For 8 of 9 genes studied in more detail, the SCF-induced polysome recruitment of transcripts exceeded 5-fold regulation and was PI3K-dependent and elF4E-sensitive, whereas total mRNA was not affected by signal transduction. One of the targets, Immunoglobulin binding protein 1 (Igbpl), is a regulatory subunit of protein phosphatase 2A (Pp2a) sustaining mTOR signaling. Constitutive expression of Igbpl impaired erythroid differentiation, maintained 4EBP and p70S6k phosphorylation, and enhanced polysome recruitment of multiple elF4E-sensitive mRNAs. Thus, PI3K-dependent polysome recruitment of Igbpl acts as a positive feedback mechanism on translation initiation underscoring the important regulatory role of selective mRNA recruitment to polysomes in the balance between proliferation and maturation of erythroblasts