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. 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. Prolactin (PRL) 1The abbreviations used are: PRLprolactinPRLRPRL receptorWTwild typeJak2Janus kinase-2Statsignal transducer and activator of transcriptionSOCS-1suppressor of cytokine signaling-1SH2Src homology 2FBSfetal bovine serumSHP-2SH2 domain-containing protein tyrosine phosphatase-2PTP1Bprotein tyrosine phosphatase-1BCAcatalytically inactive C463A mutant form of SHP-2. is a polypeptide neuroendocrine hormone that exerts a broad range of biological effects on diverse target tissues. PRL regulates different processes such as those involved in mammary gland development, reproduction, and immune regulation (reviewed by Ref. 1Goffin V. Binart N. Touraine P. Kelly P.A. Annu. Rev. Physiol. 2002; 64: 47-67Crossref PubMed Scopus (345) Google Scholar). The hormone generates its multiple biological functions by interacting with the PRL receptor (PRLR), a member of the class I cytokine receptor superfamily (2Bole-Feysot C. Goffin V. Edery M. Binart N. Kelly P.A. Endocr. Rev. 1998; 19: 225-268Crossref PubMed Scopus (1602) Google Scholar). Ligand binding to the PRLR induces receptor dimerization leading to activation of the constitutively associated Janus kinase-2 (Jak2), resulting in Jak2 and receptor tyrosine phosphorylation (3Lebrun J.J. Ali S. Sofer L. Ullrich A. Kelly P.A. J. Biol. Chem. 1994; 269: 14021-14026Abstract Full Text PDF PubMed Google Scholar, 4Lebrun J.J. Ali S. Goffin V. Ullrich A. Kelly P.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4031-4035Crossref PubMed Scopus (114) Google Scholar). These membrane-proximal signaling events play a critical role in signal propagation by recruiting effector molecules such as the signal transducer and activator of transcription-5 (Stat-5) (5Wakao H. Gouilleux F. Groner B. EMBO J. 1995; 14: 854-855Crossref PubMed Scopus (48) Google Scholar). The Jak2/Stat-5 pathway has been shown to be indispensable in mediating PRL signals, leading to various physiological responses such as terminal differentiation of mammary epithelial cells (6Groner B. Hennighausen L. Breast Cancer Res. 2000; 2: 149-153Crossref PubMed Scopus (35) Google Scholar). prolactin PRL receptor wild type Janus kinase-2 signal transducer and activator of transcription suppressor of cytokine signaling-1 Src homology 2 fetal bovine serum SH2 domain-containing protein tyrosine phosphatase-2 protein tyrosine phosphatase-1B catalytically inactive C463A mutant form of SHP-2. SHP-2, a ubiquitously expressed cytoplasmic protein tyrosine phosphatase, plays a central role in signaling downstream of receptor tyrosine kinases, G-protein-coupled receptors, and cytokine receptors including the PRLR (7Stein-Gerlach M. Wallasch C. Ullrich A. Int. J. Biochem. Cell Biol. 1998; 30: 559-566Crossref PubMed Scopus (71) Google Scholar). Following PRLR activation, SHP-2 is tyrosine-phosphorylated, physically associates to the carboxyl-terminal tyrosine of the PRLR, and is critical for activation of Stat5 and induction of the β-casein gene promoter (4Lebrun J.J. Ali S. Goffin V. Ullrich A. Kelly P.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4031-4035Crossref PubMed Scopus (114) Google Scholar, 8Ali S. Chen Z. Lebrun J.J. Vogel W. Kharitonenkov A. Kelly P.A. Ullrich A. EMBO J. 1996; 15: 135-142Crossref PubMed Scopus (128) Google Scholar, 9Ali S. J. Biol. Chem. 2000; 275: 39073-39080Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 10Berchtold S. Volarevic S. Moriggl R. Mercep M. Groner B. Mol. Endocrinol. 1998; 12: 556-567Crossref PubMed Google Scholar). The precise function of SHP-2 in PRLR signaling thus is of vital importance and has yet to be fully characterized. Modulation of Jak kinase activity has appeared as an important mechanism of regulation of cytokine receptor signaling. Studies have indicated that protein tyrosine phosphatases and adaptor/proteasomal degradation machinery are two means by which Jak2 kinase activity is regulated downstream of cytokine receptors. The protein tyrosine phosphatase SHP-1 (11Yi T. Mui A.L. Krystal G. Ihle J.N. Mol. Cell Biol. 1993; 13: 7577-7586Crossref PubMed Google Scholar, 12Klingmuller U. Lorenz U. Cantley L.C. Neel B.G. Lodish H.F. Cell. 1995; 80: 729-738Abstract Full Text PDF PubMed Scopus (842) Google Scholar), CD45 (13Irie-Sasaki J. Sasaki T. Matsumoto W. Opavsky A. Cheng M. Welstead G. Griffiths E. Krawczyk C. Richardson C.D. Aitken K. Iscove N. Koretzky G. Johnson P. Liu P. Rothstein D.M. Penninger J.M. Nature. 2001; 409: 349-354Crossref PubMed Scopus (455) Google Scholar), and PTP1B (14Aoki N. Matsuda T. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J.N. Cheng A. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. A. F. Neel B.G. Cell. 2002; 2: Full Text Full Text PDF PubMed Scopus Google Scholar, A. N. A. Cell. 2002; 2: Full Text Full Text PDF PubMed Scopus Google shown to Jak2 and cytokine receptor signaling. the of CD45 and that phosphatases the activation of Jak2 the activation of the kinase J. Matsuda T. F. Ihle J.N. Mol. Cell Biol. PubMed Scopus Google Scholar). The suppressor of cytokine signaling-1 to as R. Nature. PubMed Scopus Google Scholar, M. M. R. H. K. Matsumoto A. S. M. H. T. N. T. T. S. A. Nature. PubMed Scopus Google has been as an important of signaling pathway (reviewed in R. A. M. Richardson R. M. S. J. S. L. J. Biol. PubMed Scopus Google and J.J. M. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). is a member of the of that to and to of the a central SH2 by a carboxyl-terminal the The inhibitory role of is in to the that Jak2/SOCS-1 interaction to Jak2 kinase a as the kinase inhibitory A. H. A. S. T. Sasaki M. A. PubMed Scopus Google Scholar, H. H. H. M. Sasaki A. T. S. T. Matsuda T. Ihle J.N. A. EMBO J. PubMed Scopus Google Scholar). of its SH2 to in the activation of Jak2 to of the activity of critical role for in signaling is associated to studies have indicated that function of is to the A. Richardson R. G. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. R. M. EMBO J. PubMed Scopus Google Scholar, S. M. R. W. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). The of shown to target the gene J. J. J. Mol. Cell Biol. 2001; PubMed Scopus Google Scholar, S. T. H. S. R. M. K. S. M. S. T. H. K. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google and the wild type Jak2 P. Mol. Cell Biol. 2002; PubMed Scopus Google to and degradation on Jak2 phosphorylation on the that SHP-2 to activation of the pathway by modulating the of a Jak2 and thus the activity and of We that SHP-2 activity downstream of the PRLR by using a mutant form of the PRLR, in SHP-2 recruitment or by using a phosphatase inactive mutant of SHP-2 in a increase in Jak2 phosphorylation on and in the of a Jak2/SOCS-1 in leading to the and degradation of SHP-2 regulates PRLR signaling by recruitment site signal and the form of the PRLR and the tyrosine to mutant as as Jak2 (4Lebrun J.J. Ali S. Goffin V. Ullrich A. Kelly P.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4031-4035Crossref PubMed Scopus (114) Google Scholar). the wild type form of SHP-2 and the catalytically inactive to mutant Ullrich and an SH2 mutant by to and to Jak2 to of Jak2 and to ubiquitin and to Stat5 and SHP-2 to and to of Stat5 to and to the PRLR by Kelly by PRL used for of cells Cell and which is for by Cancer These to in fetal bovine serum and for in and with PRL blocking to to the site of with cells a of for a Cell mammary epithelial and Groner to in and to by for in and in and and by PRL cells in cells and with the form of the PRLR, and Jak2 of the cells by serum and by PRL for different of as indicated for Cell in and The by for to using the on or cells that as indicated for on for using the and protein with and on of protein or and on an of using the for using the as (4Lebrun J.J. Ali S. Goffin V. Ullrich A. Kelly P.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4031-4035Crossref PubMed Scopus (114) Google Scholar). cells with as for with the β-casein gene S. Edery M. L. J. J. Kelly P.A. Mol. Endocrinol. PubMed Scopus Google and the in and to the with and the of using the and a of different is as Prolactin Jak2/SOCS-1 to and of protein regulates the signaling of various cytokine receptors. shown to Jak2 kinase activity an interaction the SH2 of and of Jak2 H. H. H. M. Sasaki A. T. S. T. Matsuda T. Ihle J.N. A. EMBO J. PubMed Scopus Google Scholar), leading to the degradation of Jak2 J. J. J. Mol. Cell Biol. 2001; PubMed Scopus Google Scholar, S. T. H. S. R. M. K. S. M. S. T. H. K. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Mol. Cell Biol. 2002; PubMed Scopus Google Scholar). to the of in PRL signaling has been as PRLR activation to the induction of A. H. Kelly P.A. Edery M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), Jak2/SOCS-1 of activation of gene transcription S. N. Ali S. Mol. Cell. Endocrinol. PubMed Scopus Google Scholar), and of S. H. M. R. J. 2001; 15: PubMed Scopus Google Scholar). We to the association of Jak2/SOCS-1 to the and degradation of Jak2 kinase in to PRL The cells to by serum for and with PRL for the indicated in and using a to Jak2 and a the and as a on and to a using a to or a to of Jak2 indicated that PRL induces tyrosine phosphorylation of Jak2 and to by using a to Jak2 that a in Jak2 protein and to of the protein by with the to Jak2 two of which the to Jak2 in the and The of the by the to Jak2 is yet the in Jak2 protein is to the and with a to shown in as a be a by and to a We Jak2 ubiquitination/degradation in the mammary epithelial cells and that a to that in cells the indicate that PRL to a and degradation of PRL to an increase in protein the interaction Jak2 and as is to in a shown in PRL led to a increase in protein as by using a to a positive for of used as a of protein and the a with protein to PRL with the increase in by using a to Jak2 a increase in the of a Jak2/SOCS-1 PRL Jak2/SOCS-1 association and the and with a to the increase in protein the of in Jak2 protein in cells using to cells and and or with the to for an shown in the of the the increase in of the The the with an increase in the of Jak2 the different in with the the the in degradation of Jak2 blocking protein the degradation of PRLR induces a increase in by an increase in the association of leading to a and degradation of The of the PRLR the of Jak2 have that the tyrosine of the PRLR plays a vital role in the regulation of Jak2/Stat-5 signaling pathway leading to gene activation (4Lebrun J.J. Ali S. Goffin V. Ullrich A. Kelly P.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4031-4035Crossref PubMed Scopus (114) Google and is a recruitment site for SHP-2 S. J. Biol. Chem. 2000; 275: 39073-39080Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). the role of the tyrosine of the PRLR in regulating Jak2 stability. the cells with the wild type form of the PRLR or the tyrosine mutant form of the receptor in which tyrosine to with for Jak2 and We used the form of the PRLR S. Kelly P.A. J. Biol. Chem. Full Text PDF PubMed Google have shown that form is and that the is the tyrosine phosphorylation site in receptor form (4Lebrun J.J. Ali S. Goffin V. Ullrich A. Kelly P.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4031-4035Crossref PubMed Scopus (114) Google Scholar, S. Edery M. L. J. J. Kelly P.A. Mol. Endocrinol. PubMed Scopus Google and is a recruitment site for SHP-2 S. J. Biol. Chem. 2000; 275: 39073-39080Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). for with PRL for or and and for with a to shown in the protein of Jak2 the of PRL in the wild type in the tyrosine mutant form of the a in the protein of Jak2 and of PRL Jak2 the tyrosine of the PRLR plays an important role in Jak2 stability. We to protein degradation to and for that cells with the PRLR or mutant with for and shown in the for Jak2 Stat5 protein the of PRL in the different Stat5 a protein degradation as that for the results indicate that the tyrosine of the PRLR regulates the of Jak2 kinase in to PRL We the tyrosine of the PRLR regulates the interaction Jak2 and leading to the of as for and with PRL for or These of degradation of using a to and immune with a to protein PRL led to Jak2/SOCS-1 interaction in of the protein to with Jak2 in the with wild type the with a to Jak2 of Jak2 These indicate that a downstream of the tyrosine of the PRLR regulates Jak2 and to form a in to PRL degradation of associated the role of the tyrosine of the PRLR in Jak2 cells with for the wild type form of the PRLR or the tyrosine mutant of the with for and with PRL different and using a to with a to ubiquitin be PRLR activation led to Jak2 the of Jak2 a of in the tyrosine mutant form of the PRLR with the wild type PRLR Jak2 of the with a to Jak2 a of Jak2 degradation to that in a with the tyrosine of the PRLR the of be in the protein of with in the of with the tyrosine of the PRLR regulates the of Jak2 and association and Jak2/SOCS-1 and SHP-2 of Jak2/SOCS-1 and of have that the tyrosine of the PRLR is a site for SHP-2 recruitment S. J. Biol. Chem. 2000; 275: 39073-39080Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). to the regulation of Jak2 and degradation by the tyrosine of the PRLR is of the function of SHP-2. cells with for the wild type SHP-2 or a catalytically inactive mutant of SHP-2 is to with for the form of the PRLR and and with PRL for or using a to for with a to the which be protein with Jak2 PRL in the different in a association Jak2 and of the with SHP-2 wild the with a to of and in the different These indicate that SHP-2 regulates the of a Jak2/SOCS-1 downstream of the The association Jak2 and to the and degradation of We to the association Jak2 and in the of a of and degradation of that cells with for or with for the form of the PRLR and and with PRL for or Cell used for of Jak2 using a to Jak2 and with a to ubiquitin be PRL the of Jak2 in with of of the of of Jak2 associated with a in the of the on and with a to Jak2 Following PRL an in the of Jak2 in with the phosphatase SHP-2 regulates Jak2/SOCS-1 interaction the processes of and degradation of The association and Jak2 results in the of a for We SHP-2 function to in protein degradation in a to the for Jak2 We cells that with for or with for the form of the PRLR and shown in of by with a to the indicate that PRL is a in the of protein in with that of SHP-2 to the degradation of protein with the degradation of the with a to SHP-2 of SHP-2 and the role of SHP-2 in regulating the ubiquitination/degradation of in cells Jak2 with or be in in the of of Jak2 a by the of of Jak2 a in the of in which the with a to Jak2 indicated that degradation of Jak2 to with its as Jak2 protein in the of with Furthermore, of with to and SHP-2 a degradation of and protein as by the with a to Together our results indicate that the activity of SHP-2 is important in regulating the of Jak2 and its degradation with of Jak2 a for by of Jak2 is the activation in the kinase of and its phosphorylation is important for the kinase activity of Jak2 J. Matsuda T. F. Ihle J.N. Mol. Cell Biol. PubMed Scopus Google Scholar). phosphorylation of tyrosine as a recruitment site for the SH2 of leading to Jak2 kinase and and degradation H. H. H. M. Sasaki A. T. S. T. Matsuda T. Ihle J.N. A. EMBO J. PubMed Scopus Google Scholar). We SHP-2 regulation of Jak2/SOCS-1 and degradation of Jak2 are to of by the cells with for the form of the PRLR in the or the of of SHP-2. and with PRL for or on and with a of in PRL led to the phosphorylation of Jak2 on the of phosphorylation in SHP-2, that is a target for SHP-2 the with a to SHP-2 SHP-2 in the SHP-2 phosphatase dephosphorylates Jak2 on that is a for the phosphatase activity of SHP-2, cells with for or the inactive mutant with for the form of the by serum and with PRL for or and on and with a to of be in Jak2 phosphorylation PRL in of the the of phosphorylation in The with a to Jak2 and with a to SHP-2 to of protein in of the These results that of Jak2 is a for SHP-2. of of Jak2 by different phosphatases such as CD45 (13Irie-Sasaki J. Sasaki T. Matsumoto W. Opavsky A. Cheng M. Welstead G. Griffiths E. Krawczyk C. Richardson C.D. Aitken K. Iscove N. Koretzky G. Johnson P. Liu P. Rothstein D.M. Penninger J.M. Nature. 2001; 409: 349-354Crossref PubMed Scopus (455) Google and PTP1B (14Aoki N. Matsuda T. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J.N. Cheng A. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. A. F. Neel B.G. Cell. 2002; 2: Full Text Full Text PDF PubMed Scopus Google Scholar, A. N. A. Cell. 2002; 2: Full Text Full Text PDF PubMed Scopus Google have been to regulation of the kinase, the role of of Jak2 by SHP-2 on the tyrosine phosphorylation of Stat5 as an of the signaling activity of Jak2 downstream of the cells with for or with for and with PRL for or on and with a to of be in PRL tyrosine phosphorylation of Stat5 in in These studies that SHP-2 is for PRLR signaling S. Chen Z. Lebrun J.J. Vogel W. Kharitonenkov A. Kelly P.A. Ullrich A. EMBO J. 1996; 15: 135-142Crossref PubMed Scopus (128) Google Scholar, 9Ali S. J. Biol. Chem. 2000; 275: 39073-39080Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 10Berchtold S. Volarevic S. Moriggl R. Mercep M. Groner B. Mol. Endocrinol. 1998; 12: 556-567Crossref PubMed Google Scholar, N. S. Lebrun J.J. Ali S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google and the of Jak2 by SHP-2 leading to the activation of the phosphatase SHP-2 dephosphorylates Jak2 on the recruitment site for and plays a positive role in the regulation of Jak2 kinase SHP-2 of PRLR of the PRLR to the induction of gene of various gene promoter activation of the protein β-casein by is used as a of PRLR activation of signaling. regulation of Jak2/SOCS-1 interaction in PRLR signaling to gene activation, cells with or with the form of the PRLR, and the Following cells and with PRL and and shown in PRL led to the activation of the β-casein gene promoter SHP-2 led to the of PRL PRLR signaling in the of that the activity of SHP-2 of PRLR signaling to protein gene promoter a of signaling activity of the PRLR, the tyrosine phosphorylation of cells with for or with the form of the PRLR, and and with PRL for Cell on and for with a to of shown in PRL led to tyrosine phosphorylation of which by tyrosine phosphorylation of Stat5 in in the phosphatase SHP-2 its activity is to the inhibitory effects of in PRLR leading to Stat5 phosphorylation and gene promoter that SHP-2 to PRLR signaling is the regulation of Jak2/SOCS-1 used an SH2 mutant form of S. T. H. S. R. M. K. S. M. S. T. H. K. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), which the recruitment of to Jak2 in the functional We cells with or with the form of the PRLR, and the and with PRL and and shown in the that with PRL led to the activation of the β-casein gene promoter and as of Furthermore, of on gene promoter activation, that of PRLR signaling its SH2 as has been for cytokine receptor S. T. H. S. R. M. K. S. M. S. T. H. K. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). mutant with as PRLR signaling. with that the of to PRLR signaling a functional SH2 of the indicate that the positive by SHP-2 in PRLR signaling is of the of Jak2 association with We blocking recruitment to Jak2 the inhibitory effects of on Stat5 tyrosine cells with for the form of the PRLR, with or as indicated in Cell on to a and with to of tyrosine phosphorylation of Stat5 by PRL and by of Stat5 tyrosine phosphorylation in the essential role of the SH2 of in mediating the inhibitory effects of with as Stat5 with the inhibitory effects of on Stat5 tyrosine phosphorylation These results indicate that SHP-2 the signaling activity of the PRLR by regulating the interaction of thereby blocking the inhibitory effects of The of to tyrosine phosphorylation of Stat5 and β-casein gene promoter activation downstream of the PRLR led to the role of in the of shown in Jak2 in with wild type in the of or to be with wild that the degradation a functional SH2 Furthermore, that a in the of to wild type be to in as be in the using a to with a to protein the phosphatase SHP-2 is for PRLR signaling by regulating the interaction of Jak2/SOCS-1 and Jak2 regulation of signaling is critical for biological and physiological protein and phosphatases are of an of that the of signaling is that and phosphatases to and in and The protein tyrosine phosphatase SHP-2 has as an important physiological regulator of signaling of a of and the mechanism of and of SHP-2, to cytokine receptor are characterized. report a mechanism of for SHP-2 in regulating cytokine receptor which to signal We that the protein tyrosine phosphatase SHP-2 plays an essential role in regulating PRLR signaling by the activation of a recruitment site for thereby contributing to the protein of Jak2 as as its signaling results indicate that blocking SHP-2 function downstream of the PRLR by the tyrosine mutant form of the PRLR, the association site for SHP-2, as as to an of and degradation of that events are regulated by SHP-2 modulating the phosphorylation of of the interaction of our results indicate that of SHP-2 function to an increase in the degradation of that binding to Jak2 target as a to the degradation machinery associated with We are the role of SHP-2 in PRLR signaling using a in by mammary epithelial in which the of various mutant of SHP-2 are of of Jak2 is a for the activity of the kinase J. Matsuda T. F. Ihle J.N. Mol. Cell Biol. PubMed Scopus Google Scholar). results indicate that PRL is an increase in the phosphorylation of of that the tyrosine is a target for by SHP-2. that phosphorylation of of Jak2 is to a signaling of the PRLR as indicated by phosphorylation of Stat5 and activation of the β-casein gene Furthermore, the that the inhibitory effects of in PRLR signaling in the to that blocking the interaction of Jak2/SOCS-1 is a mechanism by which SHP-2 regulates PRLR signaling. our results indicate that of of Jak2 by SHP-2 is a for PRLR signal The role of phosphorylation of of Jak2 be by a of the signaling as in Following activation of cytokine receptors, Jak2 phosphorylation on to be an association site for the inhibitory protein and to the degradation of Jak2 and of the in the of the phosphatase SHP-2, of Jak2 is interacting with ubiquitination/degradation of Jak2 and the signaling of the The Jak2 is and by is that the of of Jak2 for a of The is are to a the is degradation of Jak2 by SHP-2 and with in cells and cells the of of to PRL that the of of Jak2 PRLR results the of phosphorylation of of Jak2 as a critical in the of signaling cytokine receptor The phosphatase CD45 and the cytoplasmic phosphatase PTP1B shown to of two phosphatases SHP-2 in that cytokine signaling (13Irie-Sasaki J. Sasaki T. Matsumoto W. Opavsky A. Cheng M. Welstead G. Griffiths E. Krawczyk C. Richardson C.D. Aitken K. Iscove N. Koretzky G. Johnson P. Liu P. Rothstein D.M. Penninger J.M. Nature. 2001; 409: 349-354Crossref PubMed Scopus (455) Google Scholar, J.N. Cheng A. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. A. F. Neel B.G. Cell. 2002; 2: Full Text Full Text PDF PubMed Scopus Google Scholar). The for the in the function of SHP-2 with CD45 and PTP1B is yet is to that the be to of phosphatases the be by the that CD45 and PTP1B with SHP-2. such a Jak2 be in a which to its is to the of a protein tyrosine phosphatase that in a positive the signaling of Jak2 of of the in which phosphatases in a or in which SHP-2 in a to the regulation of our is in with to signal events R. Neel B.G. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). that signal is by kinases, phosphatases have a on the and of signaling. that the protein tyrosine phosphatase SHP-2 plays a positive role in signaling the degradation of the kinase Jak2 as as the function of SHP-2 signal and by the association of Jak2 to the inhibitory protein that function of SHP-2 is to the PRLR signaling a mechanism of regulation of Jak2 by SHP-2. We for the and and Groner for the We are to and Kelly for used in We Lebrun for

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.