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The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK-STAT activation

T Iwamoto1, T Senga, Y Naito

  • 1Department of Ophthalmology, Nagoya University School of Medicine, Japan.

Oncogene
|October 14, 2000
PubMed

Insights

JAB/SOCS-1 inhibits cytokine-induced JAK-STAT signaling but not v-Src-induced activation or transformation. This suggests JAB distinguishes between these signaling pathways.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Constitutive activation of JAK kinases (JAKs) and signal transducers and activators of transcription (STATs) is observed in various cancers.
  • JAB/SOCS-1 is an intrinsic JAK tyrosine kinase inhibitor that suppresses cytokine-dependent JAK-STAT pathways.

Purpose of the Study:

  • To investigate the effect of ectopic JAB expression on v-Src-induced JAK-STAT activation.
  • To determine if JAB can suppress v-Src-induced cellular transformation.

Main Methods:

  • Forced expression of JAB in v-Src-transformed NIH3T3 cells.
  • STAT3-reporter gene activation assays.
  • Colony formation assays.
  • In vitro kinase assays.

Main Results:

  • JAB expression did not suppress STAT3 phosphorylation or STAT3-reporter gene activation in v-Src-transformed cells.
  • JAB did not inhibit v-Src-induced NIH3T3 cell transformation, unlike dominant-negative STAT3.
  • JAB downregulated STAT1 and STAT3 phosphorylation induced by interferon gamma (IFNγ) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R).
  • JAB suppressed JAK1/JAK2 hyperactivation induced by IFNγ and IL-6/sIL-6R, but not basal JAK1/JAK2 activity induced by v-Src.
  • Both v-Src-activated and IL-6/sIL-6R-activated JAK1/JAK2 could bind JAB.

Conclusions:

  • JAB/SOCS-1 distinguishes between cytokine-induced and v-Src-induced JAK-STAT signaling.
  • JAB cannot suppress v-Src-induced cellular transformation.
  • JAB's inhibitory effect is specific to cytokine-mediated JAK-STAT activation.

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