Regulation of growth hormone signaling by selective estrogen receptor modulators occurs through suppression of protein tyrosine phosphatases.

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

Breast Neoplasms

Cell Line

Tumor

Dactinomycin

pharmacology

Estrogen Antagonists

pharmacology

Estrogens

pharmacology

Human Growth Hormone

metabolism

Humans

Intracellular Signaling Peptides and Proteins

metabolism

Janus Kinase 2

metabolism

Kidney

cytology

Protein Synthesis Inhibitors

pharmacology

Protein Tyrosine Phosphatase

Non-Receptor Type 11

Protein Tyrosine Phosphatase

Non-Receptor Type 6

metabolism

Protein Tyrosine Phosphatases

metabolism

Raloxifene

pharmacology

Receptors

Estrogen

antagonists & inhibitors

metabolism

STAT5 Transcription Factor

metabolism

Signal Transduction

drug effects

physiology

Suppressor of Cytokine Signaling Proteins

metabolism

Tamoxifen

pharmacology

Publikations- och innehållstyp

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