Supplementary Materials

Supplementary Materials for:

The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation

Kate Senger, Victoria C. Pham, Eugene Varfolomeev, Jason A. Hackney, Cesar A. Corzo, Jenna Collier, Vivian W. C. Lau, Zhiyu Huang, Kajal Hamidzhadeh, Patrick Caplazi, Ivan Peng, A. Francesca Setiadi, Ross Francis, Andres Paler-Martinez, Youngsu C. Kwon, Vladimir Ramirez-Carrozzi, Yonglian Sun, Patricia W. Grigg, Merone Roose-Girma, Surinder Jeet, Kai H. Barck, Anna Pham, Naruhisa Ota, Connie Ha, Jeremy Stinson, Joseph Guillory, Lucinda Tam, Zora Modrusan, Claire Emson, Brent S. McKenzie, Michael J. Townsend, Richard A. D. Carano, Søren Warming, Domagoj Vucic, Jason DeVoss, Wyne P. Lee, Jennie R. Lill, Ali A. Zarrin*

*Corresponding author. Email: zarrin.ali{at}gene.com

This PDF file includes:

  • Fig. S1. Correlation of TPL2 abundance and activation with disease.
  • Fig. S2. Expression and catalytic activity of TPL2 in human neutrophils and monocytes.
  • Fig. S3. TPL2i specificity, validation, and PK properties.
  • Fig. S4. Kinase selectivity dendrograms of MEK and p38 inhibitors.
  • Fig. S5. Comparison of MEK1-independent, TPL2-dependent responses in human neutrophils and monocytes.
  • Fig. S6. Global phosphorylation proteomic study in human neutrophils.
  • Fig. S7. Summary of phosphotyrosine proteomic analysis of human neutrophils.
  • Fig. S8. Expression of p38 isoforms in human neutrophils and monocytes.
  • Fig. S9. Lack of effect of TPL2i on p38 signaling in human monocytes.
  • Fig. S10. Potency of p38 inhibitors and the combination of TPL2i with PH-797804 on human neutrophils.
  • Fig. S11. Validation of TPL2-KD mice with BMDMs.
  • Fig. S12. Cellular characterization and immunophenotyping of TPL2-KD mice.
  • Fig. S13. Effects of p38 or MEK inhibition on WT or TPL2-KD neutrophils.
  • Fig. S14. Reduced cytokine and chemokine production by TPL2-KD BALF cells after inhaled LPS challenge.
  • Fig. S15. Mannan-induced inflammation in TPL2-KD mice.
  • Fig. S16. A small-molecule inhibitor of TPL2 attenuates mannan-induced inflammation and collagen-induced arthritis.
  • Fig. S17. A small-molecule inhibitor of TPL2 ameliorates DSS-induced colitis in mice.
  • Legends for tables S1 to S9

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Other Supplementary Material for this manuscript includes the following:

  • Table S1 (Microsoft Excel format). Kinase selectivity profiles of TPL2i and the p38 inhibitors SB202190 and PH-797804.
  • Table S2 (Microsoft Excel format). Human monocyte gene expression data.
  • Table S3 (Microsoft Excel format). Human neutrophil gene expression data.
  • Table S4 (Microsoft Excel format). GO analysis using biological process terms of genes whose expression was specifically affected by TPL2i.
  • Table S5 (Microsoft Excel format). GO analysis using molecular function terms of genes whose expression was specifically affected by TPL2i.
  • Table S6 (Microsoft Excel format). Phosphopeptides differentially affected by TPL2i compared to vehicle control.
  • Table S7 (Microsoft Excel format). GO analysis using biological process terms of peptides differentially phosphorylated in the presence of TPL2i.
  • Table S8 (Microsoft Excel format). GO analysis using molecular function terms of peptides differentially phosphorylated in the presence of TPL2i.
  • Table S9 (Microsoft Excel format). Reactome pathway analysis of peptides differentially phosphorylated in the presence of TPL2i.

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Citation: K. Senger, V. C. Pham, E. Varfolomeev, J. A. Hackney, C. A. Corzo, J. Collier, V. W. C. Lau, Z. Huang, K. Hamidzhadeh, P. Caplazi, I. Peng, A. F. Setiadi, R. Francis, A. Paler-Martinez, Y. C. Kwon, V. Ramirez-Carrozzi, Y. Sun, P. W. Grigg, M. Roose-Girma, S. Jeet, K. H. Barck, A. Pham, N. Ota, C. Ha, J. Stinson, J. Guillory, L. Tam, Z. Modrusan, C. Emson, B. S. McKenzie, M. J. Townsend, R. A. D. Carano, S. Warming, D. Vucic, J. DeVoss, W. P. Lee, J. R. Lill, A. A. Zarrin, The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation. Sci. Signal. 10, eaah4273 (2017).

© 2017 American Association for the Advancement of Science