Upregulated flotillins and sphingosine kinase 2 derail AXL vesicular traffic to promote epithelial-mesenchymal transition

Abstract

Altered endocytosis and vesicular trafficking are major players during tumorigenesis. Flotillin overexpression, a feature observed in many invasive tumors and identified as a marker of poor prognosis, induces a deregulated endocytic and trafficking pathway called upregulated flotillin-induced trafficking (UFIT). Here, we found that in non-tumoral mammary epithelial cells, induction of the UFIT pathway promotes epithelial-to-mesenchymal transition (EMT) and accelerates the endocytosis of several transmembrane receptors, including AXL, in flotillin-positive late endosomes. AXL overexpression, frequently observed in cancer cells, is linked to EMT and metastasis formation. In flotillin-overexpressing non-tumoral mammary epithelial cells and in invasive breast carcinoma cells, we found that the UFIT pathway-mediated AXL endocytosis allows its stabilization and depends on sphingosine kinase 2, a lipid kinase recruited in flotillin-rich plasma membrane domains and endosomes. Thus, the deregulation of vesicular trafficking following flotillin upregulation, and through sphingosine kinase 2, emerges as a new mechanism of AXL overexpression and EMT-inducing signaling pathway activation.

The profile of receptor protein tyrosine kinases (RPTKs): taking AXL and DDR as examples

“…The Axl receptor is a key downstream regulator that is required for many malignant tumors to migrate and spread [13][14]. Therefore, Axl receptor overexpression is closely associated with cancer initiation and development [15].…”

Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease

“…Researchers have observed that its expression increases in subjects with Down syndrome (which are prone to develop earlier onset dementia) and AD patients [ 74 , 76 ]. Furthermore, flotillins participate in axonal regeneration [ 77 ], membrane and vesicular trafficking [ 78 ], cell migration, signal transduction, and endocytosis, which depends on the levels of phosphorylation and S-palmitoylation of the protein [ 78 , 79 , 80 ].…”

Flotillins affect LPS-induced TLR4 signaling by modulating the trafficking and abundance of CD14

“…Due to their membrane binding on the one hand and direct binding of numerous proteins on the other, homo-and hetero-oligomers of flotillins can serve as scaffolds enabling the assembly of multiprotein complexes involved in signal transduction, clathrin-/caveolin-independent endocytosis of plasma membrane proteins, and cytoskeleton remodeling [29][30][31][32][33][34]. Importantly, a growing set of recent data indicates that flotillins can also associate with endo-membranes, including the Golgi apparatus and the endo-lysosomal compartment, to take part in protein trafficking and thereby affect signaling of diverse plasma membrane receptors [35][36][37][38][39].…”