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

Abstract

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.

Tumor-derived microvesicles: The metastasomes

“…For example, cytokines, proteins, and specially (oncogenic) DNAs identified in the TDMVs [17,86,87] may play their own parts; that is actually, a complex signature (not only the RNA profiles) might be on the playground. Interestingly, an intelligent program (ExoCarta: www.exocarta.org) has recently been developed for construction of a compendium of the proteins and RNA molecules identified in the exosomes [88].…”

Involvement of serum‐derived exosomes of elderly patients with bone loss in failure of bone remodeling via alteration of exosomal bone‐related proteins

“…Various cell types secrete exosomes, which are enriched with the markers CD63 and ALG‐2‐interacting protein X (ALIX)(Choi et al., 2012). These organelles are formed solely within the endosomal network and released following fusion of multivesicular bodies with the plasma membrane (Yanez‐Mo et al., 2015).…”

141 Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells - evidence of unique microRNA cargos

“…All the scatter plots and their correlations were visualized and calculated by MATLAB. For a uniform cut-off, the distribution of gene expression in the transcriptomic data was modeled into a 2-component Gaussian mixture distribution 61,62 using gmdistribution function of MATLAB. Among two Gaussian density functions, one with lower mean intensity was annotated as "absent" peak, and the other as "present" peak.…”