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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
SHP2 regulates IL-2 induced MAPK activation, but not Stat3 or Stat5 tyrosine phosphorylation, in cutaneous T cell
Johannes Lundin Brockdorff1, Anders Woetmann, Tomas Mustelin
1Institute of Medical Microbiology and Immunology, University of Copenhagen, Blegdamsvej 3c, 2200 Copenhagen-N, Denmark.
Abstract:
The phosphotyrosine phosphatase SHP2 has been suggested to regulate activation of MAPK, Stat3, and Stat5 in several experimental models. In this study we investigated the role of SHP2 in IL-2 induced activation of MAPK and the Stat proteins using the human CTCL cell line MyLa2059 derived from a cutaneous T cell lymphoma (CTCL). For this purpose, MyLa2059 cells were stably transfected with wild-type SHP2 or inactive SHP2. The cells transfected with inactive SHP2 showed reduced MAPK activation upon IL-2 stimulation, suggesting that SHP2 upregulates IL-2 induced MAPK activation in T cells. However, the constitutive tyrosine phosphorylation of Stat3 as well as IL-2 induced Stat5 tyrosine phosphorylation and DNA binding were unaffected by the stably transfected wild-type SHP2 as well as the inactive SHP2. In conclusion, we show for the first time that SHP2 positively regulates IL-2 induced MAPK activation in malignant T cells. Furthermore, the results indicate that SHP2 may not be involved in the activation of Stat3 or Stat5 in CTCL cells.
Insights
The phosphotyrosine phosphatase SHP2 positively regulates IL-2 induced MAPK activation in malignant T cells. SHP2 does not appear to affect Stat3 or Stat5 activation in cutaneous T cell lymphoma (CTCL) cells.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- The phosphotyrosine phosphatase SHP2 is implicated in regulating cell signaling pathways.
- SHP2's role in interleukin-2 (IL-2) signaling, particularly in T cells, requires further elucidation.
- Cutaneous T cell lymphoma (CTCL) is a type of T cell malignancy where IL-2 signaling may play a role.
Purpose of the Study:
- To investigate the role of SHP2 in IL-2 induced activation of MAPK and Stat proteins.
- To determine if SHP2 regulates IL-2 signaling in the context of malignant T cells (CTCL).
Main Methods:
- Stable transfection of a human CTCL cell line (MyLa2059) with wild-type or inactive SHP2.
- Stimulation of transfected cells with IL-2.
- Assessment of MAPK, Stat3, and Stat5 activation and DNA binding.
Main Results:
- Cells expressing inactive SHP2 exhibited reduced MAPK activation following IL-2 stimulation.
- SHP2 activity positively correlates with IL-2 induced MAPK activation in CTCL cells.
- Constitutive Stat3 phosphorylation and IL-2 induced Stat5 phosphorylation/DNA binding were not affected by SHP2 manipulation.
Conclusions:
- SHP2 positively regulates IL-2 induced MAPK activation in malignant T cells.
- SHP2 does not appear to be involved in the activation of Stat3 or Stat5 in CTCL cells.
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