Jump to main content
Jump to site search
Access to RSC content Close the message box

Continue to access RSC content when you are not at your institution. Follow our step-by-step guide.

Issue 5, 2017
Previous Article Next Article

Integrative meta-modeling identifies endocytic vesicles, late endosome and the nucleus as the cellular compartments primarily directing RTK signaling

Author affiliations


Recently, intracellular receptor signaling has been identified as a key component mediating cell responses for various receptor tyrosine kinases (RTKs). However, the extent each endocytic compartment (endocytic vesicle, early endosome, recycling endosome, late endosome, lysosome and nucleus) contributes to receptor signaling has not been quantified. Furthermore, our understanding of endocytosis and receptor signaling is complicated by cell- or receptor-specific endocytosis mechanisms. Therefore, towards understanding the differential endocytic compartment signaling roles, and identifying how to achieve signal transduction control for RTKs, we delineate how endocytosis regulates RTK signaling. We achieve this via a meta-analysis across eight RTKs, integrating computational modeling with experimentally derived cell (compartment volume, trafficking kinetics and pH) and ligand–receptor (ligand/receptor concentration and interaction kinetics) physiology. Our simulations predict the abundance of signaling from eight RTKs, identifying the following hierarchy in RTK signaling: PDGFRβ > IGFR1 > EGFR > PDGFRα > VEGFR1 > VEGFR2 > Tie2 > FGFR1. We find that endocytic vesicles are the primary cell signaling compartment; over 43% of total receptor signaling occurs within the endocytic vesicle compartment for these eight RTKs. Mechanistically, we found that high RTK signaling within endocytic vesicles may be attributed to their low volume (5.3 × 10−19 L) which facilitates an enriched ligand concentration (3.2 μM per ligand molecule within the endocytic vesicle). Under the analyzed physiological conditions, we identified extracellular ligand concentration as the most sensitive parameter to change; hence the most significant one to modify when regulating absolute compartment signaling. We also found that the late endosome and nucleus compartments are important contributors to receptor signaling, where 26% and 18%, respectively, of average receptor signaling occurs across the eight RTKs. Conversely, we found very low membrane-based receptor signaling, exhibiting <1% of the total receptor signaling for these eight RTKs. Moreover, we found that nuclear translocation, mechanistically, requires late endosomal transport; when we blocked receptor trafficking from late endosomes to the nucleus we found a 57% reduction in nuclear translocation. In summary, our research has elucidated the significance of endocytic vesicles, late endosomes and the nucleus in RTK signal propagation.

Graphical abstract: Integrative meta-modeling identifies endocytic vesicles, late endosome and the nucleus as the cellular compartments primarily directing RTK signaling

Back to tab navigation

Supplementary files

Article information

13 Jan 2017
11 Apr 2017
First published
12 Apr 2017

Integr. Biol., 2017,9, 464-484
Article type

Search articles by author