Fig. 10: Model of intercellular transfer of invasiveness through endosomal protease shedding.
From: Intercellular transfer of cancer cell invasiveness via endosome-mediated protease shedding
Summarizing model: TKS4/5 are recruited to endosomes by binding to the endosomal lipid PtdIns3P and the cytosolic tail of MT1-MMP, and subsequently sorted into intraluminal vesicles of multivesicular endosomes in concert with MT1-MMP (1). TKS4/5 bridges MT1-MMP with members of the ADAM family of sheddases and the low endosomal pH facilitates ADAM-mediated cleavage of a catalytically active ectodomain of MT1-MMP in the endosome lumen (2). MT1-MMP-containing exosomes and its shed ectodomain are secreted by donor cells and dock onto MT1-MMP negative, non-invasive recipient cells (3). This induces degradation of the extracellular matrix surrounding the recipient cell. Consequently, the recipient cell becomes invasive (4). The presence of TKS4/5 in EVs could facilitate sustained MT1-MMP shedding in the acidic tumour microenvironment65. Created with BioRender.com.
