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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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T cell activation is reduced by the catalytically inactive form of protein tyrosine phosphatase SHP-2

Baoxia Dong1, Yubo Gao2, Xuan Zheng1

  • 1Department of Hematology, Xijing Hospital, Fourth Military Medical University Xi'an, Shanxi Province, China.

International Journal of Clinical and Experimental Medicine
|July 2, 2015
PubMed

Insights

Src-homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) regulates T cell activation by influencing the MAPK pathway. Overexpressing an inactive SHP-2 form reduced T cell activation, highlighting SHP-2

Area of Science:

  • Immunology
  • Cell Signaling
  • Molecular Biology

Background:

  • Src-homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) is a key enzyme in cellular signaling pathways.
  • Its role in T cell receptor (TCR) signaling and T cell activation is not fully understood.
  • SHP-2's involvement in various receptor-mediated pathways necessitates further investigation into its specific functions in T cells.

Purpose of the Study:

  • To elucidate the in vivo functional role of SHP-2 in T cell signaling.
  • To investigate the effects of inhibiting SHP-2 activity on T cell activation and downstream signaling pathways.
  • To determine SHP-2's specific contribution to TCR-mediated signaling events.

Main Methods:

  • Overexpression of a catalytically inactive mutant of SHP-2 (dnSHP-2) in mice.
  • Analysis of T cell activation markers and signaling pathway components.
  • Assessment of tyrosine phosphorylation, MAPK activity, and TCR-evoked calcium mobilization.

Main Results:

  • Mice overexpressing dnSHP-2 exhibited reduced T cell activation.
  • This reduction was associated with increased tyrosine phosphorylation of Gab2 and inhibited MAPK activity.
  • SHP-2 was identified as a positive regulator of the MAPK pathway in T cells, likely via coupling to the Ras/MAPK pathway.

Conclusions:

  • SHP-2 plays a crucial positive regulatory role in T cell activation, primarily through the MAPK pathway.
  • Inhibition of SHP-2 activity impacts T cell signaling by affecting Gab2 phosphorylation and MAPK activation.
  • SHP-2 does not appear to influence TCR-evoked calcium mobilization, SAPK/JNKs activation, or overall tyrosine phosphorylation in T cells.
Keywords:
Gab2Ras/MAPK pathwaySrc-homology 2 domain-containing tyrosine phosphatase-2T celltransgenic mice

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