Abstract
The binding of erythropoietin (EPO) to its receptor (EPO-R) activates the protein tyrosine kinase JAK2. The mechanism of JAK2 inactivation has been unclear. We show that the hematopoietic protein tyrosine phosphatase SH-PTP1 (also called HCP and PTP1C) associates via its SH2 domains with the tyrosine-phosphorylated EPO-R. In vitro binding studies suggest that Y429 in the cytoplasmic domain of the EPO-R is the binding site for SH-PTP1. Mutant EPO-Rs lacking Y429 are unable to bind SH-PTP1; cells expressing such mutants are hypersensitive to EPO and display prolonged EPO-induced autophosphorylation of JAK2. Our results suggest that activation of SH-PTP1 by binding to the EPO-R plays a major role in terminating proliferative signals.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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B-Lymphocytes
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Bone Marrow Cells
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Cell Division
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Cell Line
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Cytoplasm / metabolism
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Enzyme Activation
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Erythropoietin / metabolism
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Erythropoietin / pharmacology
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 2
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Mice
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Phosphorylation
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Point Mutation / physiology
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / metabolism*
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Protein-Tyrosine Kinases / metabolism*
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins*
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Receptors, Erythropoietin / genetics
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Receptors, Erythropoietin / metabolism*
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Recombinant Fusion Proteins / biosynthesis
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Signal Transduction / physiology*
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Tyrosine / metabolism
Substances
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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Receptors, Erythropoietin
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Recombinant Fusion Proteins
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Erythropoietin
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Tyrosine
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Protein-Tyrosine Kinases
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Jak2 protein, mouse
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Janus Kinase 2
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn6 protein, mouse