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A role for SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-dependent signaling

Ali Reja Mohammad Ruhul Amin1, Kazuya Machida, Kumi Oshima

  • 1Laboratory of Molecular Pathogenesis, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

Oncogene
|December 17, 2002
PubMed

Insights

The signaling protein SHPS-1 (SHPS-1/SIRPalpha1) is crucial for inflammatory cytokine responses. Its tyrosine phosphorylation and association with SHP-2 are required for Erk 1/2 and Akt activation by IL-1beta and TNFalpha.

Area of Science:

  • Cellular signaling pathways
  • Immunology
  • Molecular biology

Background:

  • Interleukin-1beta (IL-1beta) and Tumor Necrosis Factor-alpha (TNFalpha) are key pro-inflammatory cytokines.
  • SHPS-1/SIRPalpha1 is an immune receptor tyrosine-based inhibitory motif-containing protein.
  • Erk 1/2 and Akt are critical signaling molecules involved in cell proliferation and survival.

Purpose of the Study:

  • To investigate the role of SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-mediated signaling.
  • To elucidate the involvement of SHP-2 in SHPS-1/SIRPalpha1 downstream signaling.
  • To determine the requirement of SHPS-1/SIRPalpha1 phosphorylation and SHP-2 association for Erk 1/2 and Akt activation.

Main Methods:

  • Treatment of Balb3T3 cells with IL-1beta and TNFalpha.
  • Analysis of tyrosine phosphorylation of SHPS-1/SIRPalpha1 and its association with SHP-2 using Western blotting and co-immunoprecipitation.
  • Inhibition studies using PP1, a Src family kinase inhibitor.
  • Overexpression of wild-type and mutant SHPS-1/SIRPalpha1 and SHP-2.

Main Results:

  • IL-1beta and TNFalpha induced tyrosine phosphorylation of SHPS-1/SIRPalpha1, its association with SHP-2, and activation of Erk 1/2 and Akt.
  • PP1 inhibited SHPS-1/SIRPalpha1 phosphorylation, SHP-2 association, and Erk 1/2/Akt activation.
  • Mutant SHPS-1/SIRPalpha1 lacking SHP-2 binding or dominant-negative SHP-2 inhibited Erk 1/2/Akt activation.
  • IL-1beta stimulation induced SHPS-1/SIRPalpha1 association with IL-1RAcP, which was blocked by SHPS-1 mutants deficient in SHP-2 binding.

Conclusions:

  • SHPS-1/SIRPalpha1 tyrosine phosphorylation is essential for its association with SHP-2.
  • The SHPS-1/SIRPalpha1-SHP-2 complex is critical for IL-1beta- and TNFalpha-induced Erk 1/2 and Akt activation.
  • These findings highlight a novel signaling mechanism for pro-inflammatory cytokines involving SHPS-1/SIRPalpha1 and SHP-2.

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