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.
Ali
Samir
S
Department of Medicine, Division of Hematology and Molecular Oncology Group, Royal Victoria Hospital, McGill University, Montreal, Quebec H3A 1A1, Canada.
Nouhi
Zaynab
Z
Chughtai
Naila
N
Ali
Suhad
S
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002384:Catalysis; D002460:Cell Line; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008894:Milk Proteins; D008954:Models, Biological; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D011981:Receptors, Prolactin / Q000378:metabolism*; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism*
D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050799:STAT5 Transcription Factor; C491590:Socs1 protein, mouse; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D025801:Ubiquitin; D014443:Tyrosine; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C516727:Ptpn11 protein, rat