Epithelial-to-mesenchymal transition (EMT) is a transcriptionally governed process by which cancer cells establish a front-rear polarity axis that facilitates motility and invasion. Dynamic assembly of focal adhesions and other actin-based cytoskeletal structures on the leading edge of motile cells requires precise spatial and temporal control of protein trafficking. Yet, the way in which EMT-activating transcriptional programs interface with vesicular trafficking networks that effect cell polarity change remains unclear. Here, by utilizing multiple approaches to assess vesicular transport dynamics through endocytic recycling and retrograde trafficking pathways in lung adenocarcinoma cells at distinct positions on the EMT spectrum, we find that the EMT-activating transcription factor ZEB1 accelerates endocytosis and intracellular trafficking of plasma membrane-bound proteins. ZEB1 drives turnover of the MET receptor tyrosine kinase by hastening receptor endocytosis and transport to the lysosomal compartment for degradation. ZEB1 relieves a plus-end-directed microtubule-dependent kinesin motor protein (KIF13A) and a clathrin-associated adaptor protein complex subunit (AP1S2) from microRNA-dependent silencing, thereby accelerating cargo transport through the endocytic recycling and retrograde vesicular pathways, respectively. Depletion of KIF13A or AP1S2 mitigates ZEB1-dependent focal adhesion dynamics, front-rear axis polarization, and cancer cell motility. Thus, ZEB1-dependent transcriptional networks govern vesicular trafficking dynamics to effect cell polarity change.
|State||Published - Dec 1 2021|
Bibliographical noteFunding Information:
We thank Dr. Sandra Schmid for valuable scientific insight and Fengju Chen for technical assistance. Funding: This work was supported by the National Institutes of Health (NIH) through R01 CA181184 (to J.M.K.), R01 CA2111125 (to J.M.K.), P30 CA125123 (to C.J.C.), K99 CA225633 (to H.F.G.), NIH Lung Cancer SPORE grant P50 CA70907 (to J.M.K.), and Lung Cancer Research Foundation FP#00005299 (to X.T.). J.M.K. holds the Gloria Lupton Tennison Distinguished Endowed Professorship in Lung Cancer. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program.
© 2021, The Author(s).
ASJC Scopus subject areas
- Physics and Astronomy (all)
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)