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Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors.

Publication ,  Journal Article
Callus, BA; Mathey-Prevot, B
Published in: Blood
May 1, 1998

One facet of cytokine receptor signaling involves the activation of signal transducers and activators of transcription (STATs). STATs are rapidly activated via tyrosine phosphorylation by Janus kinase (JAK) family members and subsequently inactivated within a short period. We investigated the effect of proteasome inhibition on interleukin-3 (IL-3) activation of the JAK/STAT pathway following stimulation of Ba/F3 cells. Treatment of Ba/F3 cells with the proteasome inhibitor, N-acetyl-L-leucinyl-L-leucinyl-norleucinal (LLnL), led to stable tyrosine phosphorylation of the IL-3 receptor, beta common (betac), and STAT5 following stimulation. The effects of LLnL were not restricted to the JAK/STAT pathway, as Shc and mitogen-activated protein kinase (MAPK) phosphorylation were also prolonged in LLnL-treated cells. Further investigation showed these stable phosphorylation events were the result of prolonged activation of JAK2 and JAK1. These observations were confirmed using pharmacologic inhibitors. In the presence of LLnL, stable phosphorylation of STAT5 and betac was abrogated if the tyrosine kinase inhibitor, staurosporine, was added. The effect of staurosporine on STAT5 phosphorylation could be overcome if the phosphatase inhibitor, vanadate, was also added, suggesting phosphorylated STAT5 could be stabilized by phosphatase, but not by proteasome inhibition per se. These observations are consistent with the hypothesis that proteasome-mediated protein degradation can modulate the activity of the JAK/STAT pathway by regulating the deactivation of JAK.

Duke Scholars

Published In

Blood

ISSN

0006-4971

Publication Date

May 1, 1998

Volume

91

Issue

9

Start / End Page

3182 / 3192

Location

United States

Related Subject Headings

  • Vanadates
  • Ubiquitins
  • Trans-Activators
  • Staurosporine
  • Signal Transduction
  • STAT5 Transcription Factor
  • Receptors, Interleukin-3
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Proteasome Endopeptidase Complex
 

Citation

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MLA
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Callus, B. A., & Mathey-Prevot, B. (1998). Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors. Blood, 91(9), 3182–3192.
Callus, B. A., and B. Mathey-Prevot. “Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors.Blood 91, no. 9 (May 1, 1998): 3182–92.
Callus, B. A., and B. Mathey-Prevot. “Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors.Blood, vol. 91, no. 9, May 1998, pp. 3182–92.
Callus BA, Mathey-Prevot B. Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors. Blood. 1998 May 1;91(9):3182–3192.

Published In

Blood

ISSN

0006-4971

Publication Date

May 1, 1998

Volume

91

Issue

9

Start / End Page

3182 / 3192

Location

United States

Related Subject Headings

  • Vanadates
  • Ubiquitins
  • Trans-Activators
  • Staurosporine
  • Signal Transduction
  • STAT5 Transcription Factor
  • Receptors, Interleukin-3
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Proteasome Endopeptidase Complex