The EMT activator ZEB1 accelerates endosomal trafficking to establish a polarity axis in lung adenocarcinoma cells.
Actins
/ metabolism
Adaptor Protein Complex sigma Subunits
Adenocarcinoma of Lung
/ metabolism
Cell Line, Tumor
Cell Polarity
Cytoskeleton
/ metabolism
Endocytosis
Endosomes
/ metabolism
Epithelial-Mesenchymal Transition
/ genetics
Focal Adhesions
/ metabolism
Gene Expression Regulation, Neoplastic
Humans
Kinesins
Lung Neoplasms
/ genetics
Membrane Proteins
/ metabolism
MicroRNAs
/ metabolism
Neoplasm Metastasis
Zinc Finger E-box-Binding Homeobox 1
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 11 2021
03 11 2021
Historique:
received:
04
01
2021
accepted:
20
09
2021
entrez:
4
11
2021
pubmed:
5
11
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34732702
doi: 10.1038/s41467-021-26677-y
pii: 10.1038/s41467-021-26677-y
pmc: PMC8566461
doi:
Substances chimiques
AP1S2 protein, human
0
Actins
0
Adaptor Protein Complex sigma Subunits
0
KIF13A protein, human
0
Membrane Proteins
0
MicroRNAs
0
ZEB1 protein, human
0
Zinc Finger E-box-Binding Homeobox 1
0
Kinesins
EC 3.6.4.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6354Subventions
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA225633
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211125
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181184
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA225633
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA249048
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Informations de copyright
© 2021. The Author(s).
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