Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration

Ashley M. Lakoduk; Philippe Roudot; Marcel Mettlen; Heather M. Grossman; Sandra L Schmid; Ping Hung Chen

doi:10.1101/408815

Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration

Ashley M. Lakoduk, Philippe Roudot, Marcel Mettlen, Heather M. Grossman, Sandra L Schmid, Ping Hung Chen

Research output: Contribution to journal › Article › peer-review

Abstract

Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors. We report that gain-of-function (GOF) mutant p53 expression enhances β integrin and EGF receptor recycling and increases cell migration by triggering a positive feedback loop involving the activation of dynamin-1 (Dyn1) and accumulation of a spatially-restricted subpopulation of APPL1-positive ‘perimeter’ endosomes. DNM1 is upregulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Perimeter APPL1 endosomes are required for rapid recycling of EGFR and β1 integrins and modulate Akt signaling and Dyn1 activation to create the positive feedback loop that culminates in increased focal adhesion turnover and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus, integrating signaling and receptor trafficking, that can be co-opted by cancer cells for mutant p53-driven migration and invasion.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/408815
State	Published - Sep 5 2018

Keywords

Akt/Protein kinase B
cancer
clathrin-mediated endocytosis
EGF receptor
endocytic trafficking
invasion
signaling

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

Access to Document

10.1101/408815

Fingerprint Dive into the research topics of 'Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration'. Together they form a unique fingerprint.

Cite this

@article{d2641ee179d141d3a4d76e01dc9a33f6,

title = "Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration",

abstract = "Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors. We report that gain-of-function (GOF) mutant p53 expression enhances β integrin and EGF receptor recycling and increases cell migration by triggering a positive feedback loop involving the activation of dynamin-1 (Dyn1) and accumulation of a spatially-restricted subpopulation of APPL1-positive {\textquoteleft}perimeter{\textquoteright} endosomes. DNM1 is upregulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Perimeter APPL1 endosomes are required for rapid recycling of EGFR and β1 integrins and modulate Akt signaling and Dyn1 activation to create the positive feedback loop that culminates in increased focal adhesion turnover and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus, integrating signaling and receptor trafficking, that can be co-opted by cancer cells for mutant p53-driven migration and invasion.",

keywords = "Akt/Protein kinase B, cancer, clathrin-mediated endocytosis, EGF receptor, endocytic trafficking, invasion, signaling",

author = "Lakoduk, {Ashley M.} and Philippe Roudot and Marcel Mettlen and Grossman, {Heather M.} and Schmid, {Sandra L} and Chen, {Ping Hung}",

note = "Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2018",

month = sep,

day = "5",

doi = "10.1101/408815",

language = "English (US)",

journal = "Seminars in Fetal and Neonatal Medicine",

issn = "1744-165X",

publisher = "W.B. Saunders Ltd",

}

TY - JOUR

T1 - Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration

AU - Lakoduk, Ashley M.

AU - Roudot, Philippe

AU - Mettlen, Marcel

AU - Grossman, Heather M.

AU - Schmid, Sandra L

AU - Chen, Ping Hung

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2018/9/5

Y1 - 2018/9/5

N2 - Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors. We report that gain-of-function (GOF) mutant p53 expression enhances β integrin and EGF receptor recycling and increases cell migration by triggering a positive feedback loop involving the activation of dynamin-1 (Dyn1) and accumulation of a spatially-restricted subpopulation of APPL1-positive ‘perimeter’ endosomes. DNM1 is upregulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Perimeter APPL1 endosomes are required for rapid recycling of EGFR and β1 integrins and modulate Akt signaling and Dyn1 activation to create the positive feedback loop that culminates in increased focal adhesion turnover and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus, integrating signaling and receptor trafficking, that can be co-opted by cancer cells for mutant p53-driven migration and invasion.

AB - Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors. We report that gain-of-function (GOF) mutant p53 expression enhances β integrin and EGF receptor recycling and increases cell migration by triggering a positive feedback loop involving the activation of dynamin-1 (Dyn1) and accumulation of a spatially-restricted subpopulation of APPL1-positive ‘perimeter’ endosomes. DNM1 is upregulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Perimeter APPL1 endosomes are required for rapid recycling of EGFR and β1 integrins and modulate Akt signaling and Dyn1 activation to create the positive feedback loop that culminates in increased focal adhesion turnover and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus, integrating signaling and receptor trafficking, that can be co-opted by cancer cells for mutant p53-driven migration and invasion.

KW - Akt/Protein kinase B

KW - cancer

KW - clathrin-mediated endocytosis

KW - EGF receptor

KW - endocytic trafficking

KW - invasion

KW - signaling

UR - http://www.scopus.com/inward/record.url?scp=85095631790&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85095631790&partnerID=8YFLogxK

U2 - 10.1101/408815

DO - 10.1101/408815

M3 - Article

AN - SCOPUS:85095631790

JO - Seminars in Fetal and Neonatal Medicine

JF - Seminars in Fetal and Neonatal Medicine

SN - 1744-165X

ER -