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Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1996 Aug 06; Vol. 93 (16), pp. 8324-8. - Publication Year :
- 1996
-
Abstract
- Signaling through the erythropoietin receptor (EPO-R) is crucial for proliferation, differentiation, and survival of erythroid progenitor cells. EPO induces homodimerization of the EPO-R, triggering activation of the receptor-associated kinase JAK2 and activation of STAT5. By mutating the eight tyrosine residues in the cytosolic domain of the EPO-R, we show that either Y343 or Y401 is sufficient to mediate maximal activation of STAT5; tyrosine residues Y429 and Y431 can partially activate STAT5. Comparison of the sequences surrounding these tyrosines reveals YXXL as the probable motif specifying recruitment of STAT5 to the EPO-R. Expression of a mutant EPO-R lacking all eight tyrosine residues in the cytosolic domain supported a low but detectable level of EPO-induced STAT5 activation, indicating the existence of an alternative pathway for STAT5 activation independent of any tyrosine in the EPO-R. The kinetics of STAT5 activation and inactivation were the same, regardless of which tyrosine residue in the EPO-R mediated its activation or whether the alternative pathway was used. The ability of mutant EPO-Rs to activate STAT5 did not directly correlate with their mitogenic potential.
- Subjects :
- Amino Acid Sequence
Base Sequence
Cell Division
Cell Nucleus metabolism
Cells, Cultured
Molecular Sequence Data
Oligonucleotide Probes chemistry
Phosphotyrosine chemistry
Point Mutation
Protein Binding
Receptors, Erythropoietin chemistry
STAT5 Transcription Factor
Signal Transduction
Structure-Activity Relationship
Tyrosine chemistry
src Homology Domains
DNA-Binding Proteins metabolism
Milk Proteins
Receptors, Erythropoietin metabolism
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 93
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 8710869
- Full Text :
- https://doi.org/10.1073/pnas.93.16.8324