title: Regulation of growth hormone signaling by selective estrogen receptor modulators occurs through suppression of protein tyrosine phosphatases.
abstract: Activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) pathway by GH is terminated by the suppressors of cytokine signaling (SOCSs) and protein tyrosine phosphatases, Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 and SHP-2. Based on our recent report that estrogen inhibits GH signaling by stimulating SOCS-2 expression, we investigated the effects of selective estrogen receptor modulators (SERMs) on GH signaling in human embryonic kidney (HEK293) and breast cancer (MDA-MB-231) cells expressing human GH receptor and estrogen receptor-alpha. 17beta-estradiol (E(2)) suppressed GH activation of a STAT5-responsive luciferase reporter and JAK2 phosphorylation in both cell models. 4-hydroxytamoxifen and raloxifene augmented these actions of GH in HEK293 cells but not breast cancer cells. SOCS-2 expression in both cell types was stimulated by E(2) but unaffected by SERMs. In HEK293 cells, SHP-1 was inhibited by raloxifene and 4-hydroxytamoxifen, whereas the latter additionally inhibited SHP-2. The phosphatases were unaffected by E(2). In breast cancer cells, phosphatase activity was not altered by SERMs or E(2). In summary, estrogen inhibited the JAK2/STAT5 signaling of GH and stimulated SOCS-2 expression in both HEK293 and breast cancer cells. By contrast, SERMs augmented GH signaling by reducing SHP activities in HEK293 cells and had no effect on both in breast cancer cells. We provide the first evidence for a novel mechanism regulating GH signaling, in which SERMs enhance GH activation of the JAK2/STAT5 pathway in a cell-type-dependent manner by attenuating protein tyrosine phosphatase activities.
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. k.leung@garvan.org.au
authors.forename: Kin-Chuen
authors.initials: KC
authors.lastname: Leung
authors.forename: Jesena
authors.initials: J
authors.lastname: Brce
authors.forename: Nathan
authors.initials: N
authors.lastname: Doyle
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Lee
authors.forename: Gary M
authors.initials: GM
authors.lastname: Leong
authors.forename: Klara
authors.initials: K
authors.lastname: Sjögren
authors.forename: Ken K Y
authors.initials: KK
authors.lastname: Ho
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D011500:Protein Synthesis Inhibitors; D011960:Receptors, Estrogen; C106643:SOCS2 protein, human; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D013629:Tamoxifen; D019382:Human Growth Hormone; D003609:Dactinomycin; D020849:Raloxifene Hydrochloride; D053614:Janus Kinase 2; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases