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.

• Authors: Mallory Genest, Franck Comunale, Damien Planchon, Pauline Govindin, Dune Noly, Sophie Vacher, Ivan Bièche, Bruno Robert, Himanshu Malhotra, Andreas Schoenit, Liubov A Tashireva, Josefina Casas, Cécile Gauthier-Rouvière, Stéphane Bodin
• Journal: Journal of cell science (J Cell Sci) Vol. 135 Issue 7 (04 01 2022) ISSN: 1477-9137 [Electronic] England
• PMID: 35394045 (Publication Type: Journal Article)
• Copyright: © 2022. Published by The Company of Biologists Ltd.

Chemical References

• Membrane Proteins
• Proto-Oncogene Proteins
• flotillins
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase 2, human
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase
• AXL protein, human

Topics

• Breast Neoplasms
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Membrane Proteins (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Axl Receptor Tyrosine Kinase