PhosY-secretome profiling combined with kinase-substrate interaction screening defines active c-Src-driven extracellular signaling.

ABSTRACT: c-Src tyrosine kinase is a renowned key intracellular signaling molecule and a potential target for cancer therapy. Secreted c-Src is a recent observation, but how it contributes to extracellular phosphorylation remains elusive. Using a series of domain deletion mutants, we show that the N-proximal region of c-Src is essential for its secretion. The tissue inhibitor of metalloproteinases 2 (TIMP2) is an extracellular substrate of c-Src. Limited proteolysis-coupled mass spectrometry and mutagenesis studies verify that the Src homology 3 (SH3) domain of c-Src and the P³¹VHP³⁴ motif of TIMP2 are critical for their interaction. Comparative phosphoproteomic analyses identify an enrichment of PxxP motifs in phosY-containing secretomes from c-Src-expressing cells with cancer

SUBMITTER: Backe SJ 

PROVIDER: S-EPMC10569185 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature