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Tyrosine phosphorylation of the erythropoietin receptor: role for
differentiation and mitogenic signal transduction
S Gobert, F Porteu, S Pallu, O Muller, M Sabbah, I Dusanter-Fourt, G Courtois, C Lacombe, S Gisselbrecht and P Mayeux
Institut Cochin de Genetique Moleculaire (ICGM), Universite Rene Descartes,
Paris, France.
The erythropoietin (Epo) receptor belongs to the cytokine receptor
superfamily. Although the cytokine receptors do not possess a tyrosine
kinase consensus sequence in the intracellular domain, rapid stimulation of
a tyrosine kinase activity occurs after activation by the ligand. We and
others have shown that Epo induces the tyrosine phosphorylation of its
cognate receptor as well as phosphorylation of other proteins. In this
report, we examined the role of the receptor tyrosine residues in signal
transduction. Eight tyrosine residues are located within the intracellular
domain of the murine Epo receptor. A single tyrosine residue is present in
the region previously shown to be sufficient for proliferative signal
transduction. This tyrosine (Tyr 343) was mutated to phenylalanine.
Moreover, mutant receptors were also generated with either a tyrosine
residue or a phenylalanine residue at position 343 and with a COOH terminal
truncation that removed the 7 other tyrosine residues. Expression vectors
carrying these mutated receptors were transfected into the
interleukin-3-dependent murine cell line Ba/F3. Epo-induced growth was
sustained efficiently by all these receptors, although receptors without
any tyrosine residues conferred a significantly reduced mitogenic activity.
Moreover, all receptors were able to mediate Epo-dependant accumulation of
beta-globin mRNA. The mutated receptors all induced the tyrosine
phosphorylation of several cellular proteins after Epo stimulation.
However, the truncated receptors induced the phosphorylation of a reduced
number of proteins, suggesting that phosphorylated tyrosines of the
receptor could have a role in the recruitment either of a tyrosine kinase
or of tyrosine kinase substrate proteins. The receptors were all able to
mediate Epo- induced activation of phosphatidylinositol 3-kinase, although
truncated receptors no longer bound phosphatidylinositol 3-kinase.
Volume 86,
Issue 2,
pp. 598-606,
07/15/1995
Copyright © 1995 by The American Society of Hematology
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