IGF-1R modulation of acute GH-induced STAT5 signaling: Role of protein tyrosine phosphatase activity

Yujun Gan, Yue Zhang, Ashiya Buckels, Andrew J. Paterson, Jing Jiang, Thomas L. Clemens, Zhong Yin Zhang, Keyong Du, Yingzi Chang, Stuart J. Frank

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

GH is a potent anabolic and metabolic factor that binds its cell surface receptor (GHR), activating the GHR-associated tyrosine kinase, Janus kinase 2, which phosphorylates and activates the latent transcription factor, signal transducer and activator of transcription 5 (STAT5). Some GH actions are mediated by the elaboration of IGF-1, which exerts effects by binding and activating the heterotetrameric tyrosine kinase growth factor receptor, IGF-1R. In addition to this GH-GHR-IGF-1-IGF-1R scheme, we have demonstrated in primary osteoblasts and in islet β-cells that then deletion or silencing of IGF-1R results in diminished GH-induced STAT5 phosphorylation, suggesting that the presence of IGF-1R may facilitate GH signaling. In this study, we explore potential roles for protein tyrosine phosphatase activity in modulating GH-induced signaling, comparing conditions in which IGF-1R is present or diminished. We confirm that in mouse primary osteoblasts harboring loxP sites flanking the IGF-1R gene, infection with an adenovirus that expresses the Cre recombinase results in IGF-1R deletion and diminished acute GH-induced STAT5 phosphorylation. Furthermore, we present a new model of IGF-1R silencing, in which expression of short hairpin RNA directed at IGF-1R greatly reduces IGF-1R abundance in LNCaP human prostate cancer cells. In both models, treatment with a chemical inhibitor of protein tyrosine phosphatase-1B (PTP-1B), but not one of src homology region 2 domain-containing phosphotase-1 (SHP-1) and SHP-2, reverses the loss of GH-induced STAT5 phosphorylation in cells lacking IGF-1R but has no effect in cells with intact IGF-1R. Furthermore, expression of either a dominant-negative PTP-1B or the PTP-1B-interacting inhibitory protein, constitutive photomorphogenesis 1, also rescues acute GH-induced STAT5 signaling in IGF-1R-deficient cells but has no effect in IGF-1R replete cells. By expressing a substrate-trapping mutant PTP-1B, we demonstrate that tyrosine phosphorylated Janus kinase-2 is a PTP-1B substrate only in cells lacking IGF-1R. Collectively, our data suggest that IGF-1R positively regulates acute GH signaling by preventing access of PTP-1B activity to Janus kinase 2 and thereby preventing PTP-1B-mediated suppression of GH-induced STAT5 activation.

Original languageEnglish (US)
Pages (from-to)1969-1979
Number of pages11
JournalMolecular Endocrinology
Volume27
Issue number11
DOIs
StatePublished - Oct 30 2013

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
STAT5 Transcription Factor
Protein Tyrosine Phosphatases
Janus Kinase 2
Phosphorylation
Osteoblasts
Insulin-Like Growth Factor I
Protein-Tyrosine Kinases
Adenoviridae Infections
src Homology Domains
Growth Factor Receptors
Cell Surface Receptors
Mutant Proteins
Islets of Langerhans
Small Interfering RNA
Transcriptional Activation
Tyrosine
Prostatic Neoplasms
Transcription Factors

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Gan, Y., Zhang, Y., Buckels, A., Paterson, A. J., Jiang, J., Clemens, T. L., ... Frank, S. J. (2013). IGF-1R modulation of acute GH-induced STAT5 signaling: Role of protein tyrosine phosphatase activity. Molecular Endocrinology, 27(11), 1969-1979. https://doi.org/10.1210/me.2013-1178

IGF-1R modulation of acute GH-induced STAT5 signaling : Role of protein tyrosine phosphatase activity. / Gan, Yujun; Zhang, Yue; Buckels, Ashiya; Paterson, Andrew J.; Jiang, Jing; Clemens, Thomas L.; Zhang, Zhong Yin; Du, Keyong; Chang, Yingzi; Frank, Stuart J.

In: Molecular Endocrinology, Vol. 27, No. 11, 30.10.2013, p. 1969-1979.

Research output: Contribution to journalArticle

Gan, Y, Zhang, Y, Buckels, A, Paterson, AJ, Jiang, J, Clemens, TL, Zhang, ZY, Du, K, Chang, Y & Frank, SJ 2013, 'IGF-1R modulation of acute GH-induced STAT5 signaling: Role of protein tyrosine phosphatase activity', Molecular Endocrinology, vol. 27, no. 11, pp. 1969-1979. https://doi.org/10.1210/me.2013-1178
Gan, Yujun ; Zhang, Yue ; Buckels, Ashiya ; Paterson, Andrew J. ; Jiang, Jing ; Clemens, Thomas L. ; Zhang, Zhong Yin ; Du, Keyong ; Chang, Yingzi ; Frank, Stuart J. / IGF-1R modulation of acute GH-induced STAT5 signaling : Role of protein tyrosine phosphatase activity. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 11. pp. 1969-1979.
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