A Back-Door Insights into the modulation of Src kinase activity by the polyamine spermidine

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.

Advanced age and female sex protect cerebral arteries from mitochondrial depolarization and apoptosis during acute oxidative stress

“…To further characterize the role of Src kinases in mediating cell death, we activated Src kinases with spermidine (Rossini et al., 2023). Spermidine (100 μM; 50 min) evoked minimal (<10%) SMC death in young and old males (Figure 6b) and females (Figure 6c).…”

“…The polyamine spermidine (100 μM; Cat. #AC132740050, Fisher) was utilized to activate Src kinases (Rossini et al., 2023). Controls include respective vehicles added to PSS without the pharmacological agent.…”

“…In PCAs from female mice, Src kinase inhibition had no effect on the low prevailing SMC death (Figure 5b). There was no effect of SU6656 on the low prevailing EC death in vessels from any group (Figure 5c,d To further characterize the role of Src kinases in mediating cell death, we activated Src kinases with spermidine (Rossini et al, 2023). Spermidine (100 μM; 50 min) evoked minimal (<10%) SMC death in young and old males (Figure 6b) and females (Figure 6c).…”

“…The polyamine spermidine (100 μM; Cat. #AC132740050, Fisher) was utilized to activate Src kinases (Rossini et al, 2023).…”