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Signaling Functions of the Tyrosine Residues in the  c Chain of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor
Keiko Okuda,
Lorie Smith,
James D. Griffin, and
Rosemary Foster
From the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and the Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA.
The granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR) is a heterodimeric receptor expressed by myeloid lineage cells. Binding of GM-CSF activates at least one receptor-associated tyrosine kinase, JAK2, and rapidly induces tyrosine phosphorylation of the GMR  c-chain (GMR), but not the GMR  -chain (GMR). To examine the role of GMR tyrosine phosphorylaiton, each of the 8 tyrosine residues in the cytoplasmic domain of the human GMR was mutated to phenylalanine (GMR-F8), and this mutant receptor was expressed with wild-type GMR in the interleukin-3-dependent murine hematopoietic cell line, Ba/F3. GM-CSF induced tyrosine phosphorylation of multiple cellular proteins in cells expressing GMR-F8 , including JAK2 and STAT5. However, GM-CSF-induced tyrosine phosphorylation of both SHP2 and SHC was reduced or absent compared with wild-type. Next, a series of 8 receptors were generated, each containing only a single, restored, tyrosine residue. Tyrosine 577 was found to be sufficient to regenerate GM-CSF-dependent phosphorylation of SHC, and any of Y577, Y612, or Y695 was sufficient to regenerate GM-CSF-inducible phosphorylation of SHP2. Despite the signaling defect to SHC and SHP2, Ba/F3 cells expressing GMR-F8 were still able to proliferate in response to 10 ng/mL of human GM-CSF, although mitogenesis was impaired compared with wild-type GMR, and this effect was even more prominent at lower concentrations of GM-CSF (1 ng/mL). Overall, these results indicate that GMR tyrosine residues are not necessary for activation of the JAK/STAT pathway or for proliferation, viability, or adhesion signaling in Ba/F3 cells, although tyrosine residues significantly affect the magnitude of the response. However, specific tyrosine residues are needed for activation of SHC and SHP2.
Blood, Vol. 90 No. 12 (December 15), 1997:
pp. 4759-4766
© 1997 by The American Society of Hematology.
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