Inhibitory Roles for SHP-1 and SOCS-3 Following Pituitary Proopiomelanocortin Induction by Leukemia Inhibitory Factor

J Clin Invest. 1999 Nov;104(9):1277-85. doi: 10.1172/JCI7924.

Abstract

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that stimulates the hypothalamo-pituitary-adrenal (HPA) axis through JAK-STAT activation. We show here that LIF-induced JAK2 and STAT3 tyrosine phosphorylation is transient, disappearing within 20 and 40 minutes, respectively. LIF activates the SH2 domain-containing tyrosine phosphatase, SHP-1, with maximal stimulation observed at 30 minutes. SHP-1 is constitutively associated with JAK2, and LIF induces recruitment of phosphorylated STAT3 to this complex. Overexpression of wild-type or dominant negative forms of SHP-1 shows decreased or increased LIF-induced proopiomelanocortin (POMC) promoter activity, respectively. LIF-induced JAK2 and STAT3 dephosphorylation is delayed until after 60 minutes in cells that overexpress the mutant SHP-1. In addition, SOCS-3, a negative regulator of LIF signaling, binds to JAK2 after 60 minutes of LIF stimulation, after which the complex is degraded by the proteasome. SOCS-3 overexpression blocks LIF-induced JAK2 tyrosine phosphorylation, confirming a role for SOCS-3 in deactivating JAK2 by direct association. Using SOCS-3 fusion proteins, we also define regions of the SOCS-3 protein that are critical for inhibition of LIF-induced POMC promoter activity. Corticotrophic signaling by LIF is thus subject to 2 forms of negative autoregulation: dephosphorylation of JAK2 and STAT3 by the SHP-1 tyrosine phosphatase, and SOCS-3-dependent inactivation of JAK2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Catalysis
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Growth Inhibitors / pharmacology*
  • Interleukin-6*
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 2
  • Leukemia Inhibitory Factor
  • Lymphokines / pharmacology*
  • Mice
  • Models, Biological
  • Phosphorylation
  • Pituitary Gland / metabolism*
  • Pro-Opiomelanocortin / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism
  • Protein Tyrosine Phosphatases / physiology*
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / physiology*
  • Proto-Oncogene Proteins*
  • Repressor Proteins*
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • STAT3 Transcription Factor
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Time Factors
  • Trans-Activators / metabolism
  • Transcription Factors*
  • Transfection

Substances

  • DNA-Binding Proteins
  • Growth Inhibitors
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • Lymphokines
  • Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • Pro-Opiomelanocortin
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse
  • SH2 Domain-Containing Protein Tyrosine Phosphatases