Endocytosis‐dependent lysosomal degradation of Src induced by protease‐activated receptor 1

Abstract

Src plays a critical role in regulating cellular responses induced by protease‐activated receptor 1 (PAR1). Here, we found that PAR1 activation induces lysosomal degradation of Src. Src is associated and trafficked together with activated PAR1 to early endosomes and then sorted to lysosomes for degradation. Blocking agonist‐induced endocytosis of PAR1 by inhibition of dynamin activity suppresses PAR1‐induced degradation of Src. However, Src activity is neither required for agonist‐induced PAR1 internalization nor required for Src degradation upon PAR1 activation. We show that PAR1 activation triggers endocytosis‐dependent lysosomal degradation of Src in both human embryonic kidney 293 and human umbilical vein endothelial cells. Our finding provides a new paradigm for how an irreversibly activated receptor regulates its downstream signalling.

A TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration

“…During post-transcriptional regulation, miRNAs directly bind to SRC mRNA, resulting in the degradation and inhibition of SRC mRNA translation ( Majid et al, 2011 ; Okuzaki et al, 2020 ; Oneyama and Okada, 2015 ; Wang et al, 2014 ). Also, the specific activity of SRC is regulated by C-terminal regulatory phosphorylation ( Nada et al, 1991 ; Okada, 2012 ), and its protein level is regulated by degradation via the lysosome ( Tsai et al, 2019 ) and proteasome ( Kim et al, 2004 ; Mukhopadhyay et al, 2016 ) systems, or by excretion via small extracellular vesicles ( Tanaka et al, 2020 ). In this study, we focused on the transcriptional regulation of SRC .…”

A novel TGF-β-responsive enhancer regulates SRC expression and epithelial–mesenchymal transition-associated cell migration

“…In post-transcriptional regulation, miRNAs directly bind to SRC mRNA, resulting in the degradation and inhibition of SRC mRNA translation (Majid et al, 2011;Okuzaki et al, 2020;Oneyama and Okada, 2015;Wang et al, 2014). In post-transcriptional regulation, the specific activity of SRC is regulated by C-terminal regulatory phosphorylation (Nada et al, 1991;Okada, 2012), and its protein level is regulated by degradation via the lysosome (Tsai et al, 2019) and proteasome (Kim et al, 2004;Mukhopadhyay et al, 2016) systems or by excretion via small extracellular vesicles (Tanaka et al, 2020).…”

“…In post-transcriptional regulation, miRNAs directly bind to SRC mRNA, resulting in the degradation and inhibition of SRC mRNA translation (Majid et al, 2011; Okuzaki et al, 2020; Oneyama and Okada, 2015; Wang et al, 2014). In post-transcriptional regulation, the specific activity of SRC is regulated by C-terminal regulatory phosphorylation (Nada et al, 1991; Okada, 2012), and its protein level is regulated by degradation via the lysosome (Tsai et al, 2019) and proteasome (Kim et al, 2004; Mukhopadhyay et al, 2016) systems or by excretion via small extracellular vesicles (Tanaka et al, 2020). In this study, we focused on the transcriptional regulatory systems of SRC .…”