The Protein Interaction Network of Extracellular Vesicles Derived from Human Colorectal Cancer Cells

Various mammalian cells including tumor cells secrete
extracellular
vesicles (EVs), otherwise known as exosomes and microvesicles. EVs
are nanosized bilayered proteolipids and play multiple roles in intercellular
communication. Although many vesicular proteins have been identified,
their functional interrelationships and the mechanisms of EV biogenesis
remain unknown. By interrogating proteomic data using systems approaches,
we have created a protein interaction network of human colorectal
cancer cell-derived EVs which comprises 1491 interactions between
957 vesicular proteins. We discovered that EVs have well-connected
clusters with several hub proteins similar to other subcellular networks.
We also experimentally validated that direct protein interactions
between cellular proteins may be involved in protein sorting during
EV formation. Moreover, physically and functionally interconnected
protein complexes form functional modules involved in EV biogenesis
and functions. Specifically, we discovered that SRC signaling plays
a major role in EV biogenesis, and confirmed that inhibition of SRC
kinase decreased the intracellular biogenesis and cell surface release
of EVs. Our study provides global insights into the cargo-sorting,
biogenesis, and pathophysiological roles of these complex extracellular
organelles.