Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals

Cell. 1995 Mar 10;80(5):729-38. doi: 10.1016/0092-8674(95)90351-8.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes
  • Bone Marrow Cells
  • Cell Division
  • Cell Line
  • Cytoplasm / metabolism
  • Enzyme Activation
  • Erythropoietin / metabolism
  • Erythropoietin / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 2
  • Mice
  • Phosphorylation
  • Point Mutation / physiology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins*
  • Receptors, Erythropoietin / genetics
  • Receptors, Erythropoietin / metabolism*
  • Recombinant Fusion Proteins / biosynthesis
  • Signal Transduction / physiology*
  • Tyrosine / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Receptors, Erythropoietin
  • Recombinant Fusion Proteins
  • Erythropoietin
  • Tyrosine
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse