G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact
Truncated granulocyte colony-stimulating factor receptors (G-CSF-Rs) are implicated in severe congenital neutropenia (SCN) and the consecutive development of acute myeloid leukemia (AML). Mice expressing G-CSF-R truncation mutants (gcsfr-d715) show defective receptor internalization, an increased signal transducer and activator of transcription 5 (STAT5)/STAT3 activation ratio, and hyperproliferative responses to G-CSF treatment. We determined whether a lack of negative feedback by suppressor of cytokine signaling (SOCS) proteins contributes to the signaling abnormalities of G-CSF-R-d715. Expression of SOCS3 transcripts in bone marrow cells from G-CSF-treated gcsfr-d715 mice was approximately 60% lower than in wild-type (WT) littermates. SOCS3 efficiently suppressed STAT3 and STAT5 activation by WT G-CSF-R in luciferase reporter assays. In contrast, while SOCS3 still inhibited STAT3 activation by G-CSF-R-d715, STAT5 activation was no longer affected. This was due mainly to loss of the SOCS3 recruitment site Tyr729, with an additional contribution of the internalization defects of G-CSF-R-d715. Because Tyr729 is also a docking site for the Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2), which binds to and inactivates STAT5, we suggest a model in which reduced SOCS3 expression, combined with the loss of recruitment of both SOCS3 and SHP-2 to the activated receptor complex, determine the increased STAT5/STAT3 activation ratio and the resulting signaling abnormalities projected by truncated G-CSF-R mutants.
|Keywords||*Milk Proteins, *Sequence Deletion, Amino Acid Sequence, Animals, Binding Sites, DNA-Binding Proteins/antagonists & inhibitors/genetics/*physiology, Disease Models, Animal, Humans, Leukemia, Myelocytic, Acute/*genetics, Mice, Mice, Mutant Strains, Neutropenia/*genetics, Receptors, Granulocyte Colony-Stimulating Factor/*genetics/physiology, Repressor Proteins/genetics/*physiology, Research Support, Non-U.S. Gov't, STAT3 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators/antagonists & inhibitors/genetics/*physiology, Transcription Factors/genetics/*physiology, Tyrosine, src Homology Domains|
Gits, J., Aarts, L.H.J., Heijmans-Antonissen, C., Touw, I.P., & van de Geijn, G.J.M.. (2004). G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact. Blood. Retrieved from http://hdl.handle.net/1765/8160