Spatio-Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options

Abstract

The endo/lysosomal system in cells provides membranous platforms to assemble specific signaling complexes and to terminate signal transduction, thus, is essential for physiological signaling. Endocytic organelles can significantly extend signaling of activated cell surface receptors, and may additionally provide distinct locations for the generation of specific signaling outputs. Failures of regulation at different levels of endocytosis, recycling, degradation as well as aberrations in specific endo/lysosomal signaling pathways, such as mTORC1, might lead to different diseases including cancer. Therefore, a better understanding of spatio-temporal compartmentalization of sub-cellular signaling might provide an opportunity to interfere with aberrant signal transduction in pathological processes by novel combinatorial therapeutic approaches.

Keywords: CANCER; ENDOSOME; LYSOSOME; SCAFFOLDS; SIGNALING.

Figure 1

Druggable points of oncogenic endo/lysosomal signaling. Receptor‐mediated signal transduction is deregulated in human tumors at different levels of receptor activation and trafficking, labeled here with red arrows. Oncogenic mutations in different receptors result in increased recycling and in a decrease in the degradation of the receptors. Increased recycling of activated receptors is delineated in the scheme with bold arrows. In addition to conventional anticancer therapies employing, e.g., tyrosine kinase inhibitors (I), novel combinatorial approaches could interfere with endo/lysosomal signaling and/or aberrant receptor trafficking at the levels of receptor internalization (II), early endosomal signaling (III), receptor recycling back to the plasma membrane via recycling endosomes (IV), signaling from late endosomes (V) or lysosomes (VI). Endosomal adaptor and scaffold proteins, which organize signaling complexes in the organelles and molecular sorting machineries that determine receptor trafficking (shown in green) could be potential anticancer targets. ASRT, actin‐sorting nexin 27‐retromer tubule; EE, early endosome; LE/MVB, late endosome/multivesicular body; LY, lysosome; PM, plasma membrane; RE, recycling endosome.