Flotillins in receptor tyrosine kinase signaling and cancer

Abstract

Flotillins are highly conserved proteins that localize into specific cholesterol rich microdomains in cellular membranes. They have been shown to be associated with, for example, various signaling pathways, cell adhesion, membrane trafficking and axonal growth. Recent findings have revealed that flotillins are frequently overexpressed in various types of human cancers. We here review the suggested functions of flotillins during receptor tyrosine kinase signaling and in cancer. Although flotillins have been implicated as putative cancer therapy targets, we here show that great caution is required since flotillin ablation may result in effects that increase instead of decrease the activity of specific signaling pathways. On the other hand, as flotillin overexpression appears to be related with metastasis formation in certain cancers, we also discuss the implications of these findings for future therapy aspects.

Figure 1

Modifications of flotillins upon epidermal growth factor (EGF) stimulation. Flotillins undergo modifications during RTK signaling. In addition to tyrosine phosphorylation upon EGF stimulation, flotillin hetero-oligomers increase in size and translocate to late endosomes.

Figure 2

Flotillins in EGFR activation/clustering. While EGF stimulation of control cells induces EGFR activation, tyrosine phosphorylation and clustering of the receptor, cells depleted of flotillin-1 show a reduced tyrosine phosphorylation. Already in unstimulated cells, preformed EGFR clusters that do not increase in size upon EGF stimulation are observed in the absence of flotillin-1.