The EMT activator ZEB1 accelerates endosomal trafficking to establish a polarity axis in lung adenocarcinoma cells

Abstract

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.

Electrical charge on ferroelectric nanocomposite membranes enhances SHED neural differentiation

“…4 f). In particular, the neurogenesis-related ErbB signaling pathway [ 44 ], cell focal adhesion-related pathways [ 45 , 46 ], and the regulation of actin cytoskeleton [ 47 ] were all found to be enriched ( Fig. 4 g).…”

Functional mechanism of hsa-miR-128-3p in epithelial-mesenchymal transition of pancreatic cancer cells via ZEB1 regulation

“…It’s been reported that EMT is a pivotal step in the invasion and metastasis of PC cells ( Li et al., 2020 ; Rhim et al., 2012 ; Zhou et al., 2017 ). ZEB1 is a key transcriptional factor in EMT activation ( Banerjee et al., 2021 ; Garinet et al., 2021 ). There is evidence that miR-128-3p inhibits metastasis and EMT in esophageal squamous-cell cancer via targeting ZEB1 ( Zhao et al., 2018 ).…”

KIF13A—A Key Regulator of Recycling Endosome Dynamics

“…Since endocytic recycling is essential for cellular homeostasis, defects therein can lead to maladies. Dysfunction of KIF13A has been implicated in many cancers ( Gong et al, 2018 ; Zhang et al, 2018 ; Banerjee et al, 2021 ), and its enhanced amplification is observed in some cancers ( Chandrasekaran et al, 2015 ). A KIF13A fusion with RET sequences encoding tyrosine kinase (KIF13-RET) has been reported in lung adenocarcinoma ( Zhang et al, 2018 ).…”

“…Interestingly, KIF13A was observed to mislocalize from the Golgi region to the nucleus during glioma progression ( Lee et al, 2013 ). Transcriptional regulation of KIF13A by epithelial-to-mesenchymal transcription factors has been found to promote trafficking through endosomal recycling, which facilitates the establishment of a polarity axis during cell migration and has been found to be essential for cancer progression in lung adenocarcinoma cells ( Banerjee et al, 2021 ). In neuronal cells, the absence of KIF13A causes reduced cell surface expression of a set of serotonin receptors, leading to elevated anxiety phenotype in KIF13A knockout mice ( Zhou et al, 2013 ).…”