SHP-2 regulates SOCS-1-mediated Janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor.
The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine ... signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.
Mesh Terms:
Animals, Blotting, Western, Carrier Proteins, Catalysis, Cell Line, Cell Line, Tumor, DNA, Complementary, DNA-Binding Proteins, Gene Expression Regulation, Humans, Intracellular Signaling Peptides and Proteins, Janus Kinase 2, Luciferases, Mice, Milk Proteins, Models, Biological, Mutation, Oligonucleotides, Antisense, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Rats, Receptors, Prolactin, Repressor Proteins, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Time Factors, Trans-Activators, Transfection, Tyrosine, Ubiquitin
Animals, Blotting, Western, Carrier Proteins, Catalysis, Cell Line, Cell Line, Tumor, DNA, Complementary, DNA-Binding Proteins, Gene Expression Regulation, Humans, Intracellular Signaling Peptides and Proteins, Janus Kinase 2, Luciferases, Mice, Milk Proteins, Models, Biological, Mutation, Oligonucleotides, Antisense, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Rats, Receptors, Prolactin, Repressor Proteins, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Time Factors, Trans-Activators, Transfection, Tyrosine, Ubiquitin
J. Biol. Chem.
Date: Dec. 26, 2003
PubMed ID: 14522994
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