Src in endosomal membranes promotes exosome secretion and tumor progression

• Published in: Scientific reports Vol. 9; no. 1; p. 3265
• Main Authors: Hikita, Tomoya, Kuwahara, Atsushi, Watanabe, Risayo, Miyata, Mamiko, Oneyama, Chitose
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2019; Nature Publishing Group
• Subjects: 14/1; 14/35; 38/109; 38/89; 631/67/395; 631/80/86; Cancer; Carcinogenesis; Cell migration; Exosomes; Humanities and Social Sciences; Kinases; Membranes; multidisciplinary; Phenotypes; Proline; Protein-tyrosine kinase; Science; Science (multidisciplinary); Signal transduction; Src protein; Transformed cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-39882-z

c-Src is a membrane-associated tyrosine kinase that has key roles in the signaling transduction that controls cell growth, adhesion, and migration. In the early stage of carcinogenesis, c-Src is activated under the plasma membrane and transduces oncogenic signals. Here we show that c-Src localized to the endosomal membrane has unique functions in c-Src–transformed cells. Our results indicate that activated c-Src in the endosomal membrane promoted the secretion of exosomes, in which c-Src was encapsulated. In addition, the ESCRT-interacting molecule, Alix was identified as a c-Src–interacting protein in exosomes. We revealed that the interaction between the SH3 domain of c-Src and the proline-rich region of Alix activates ESCRT–mediated intra-luminal vesicle (ILV) formation, resulting in the upregulation of exosome secretion in c-Src–transformed cells. We observed also a correlation between malignant phenotypes and Alix–dependent aberrant exosome secretion in Src–upregulated cancer cells. Collectively, our findings provide a unique mechanism for the upregulation of exosomes in cancer cells, as well as new insights into the significance of exosome secretion in cancer progression.