A back-door insights into the modulation of Src kinase activity by the polyamine spermidine
- University of Perugia, Italy
Abstract
Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration and survival signaling pathways. In conventional dendritic cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein-protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file.Figure 1 - Source Data 1; Figure 1 - Source Data 2; Figure 1 - Figure supplement 1 - Source Data 3; Figure 2 - Source Data 4; Figure 2 - Figure supplement 1 - Source Data 5; Figure 2 - Figure supplement 2 - Source Data 6; Figure 3 - Source Data 7; Figure 3 - Source Data 8; Figure 3 - Source Data 9; Figure 3 - Source Data 10; Figure 3 - Source Data 11; Figure 3 - Figure supplement 1 - Source Data 12: contain the original blots used to generate the figures.
Article and author information
Author details
Funding
Università degli Studi di Perugia (Ricerca di base 2019)
- Giada Mondanelli
Associazione italiana per la ricerca sul cancro (AIRC 2019-23084)
- Claudia Volpi
Italian Ministry of Education, University, and Research (PRIN 2020L45ZW)
- Ciriana Orabona
Università degli Studi di Perugia (Ricerca di base 2020)
- Antonio Macchiarulo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Rossini et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A back-door insights into the modulation of Src kinase activity by the polyamine spermidine
eLife 12:e85872.
https://doi.org/10.7554/eLife.85872
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