EGF receptor-mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling.

The Journal of Cell Biology
Manuel ChiusaAmbra Pozzi

Abstract

Excessive accumulation of collagen leads to fibrosis. Integrin α1β1 (Itgα1β1) prevents kidney fibrosis by reducing collagen production through inhibition of the EGF receptor (EGFR) that phosphorylates cytoplasmic and nuclear proteins. To elucidate how the Itgα1β1/EGFR axis controls collagen synthesis, we analyzed the levels of nuclear tyrosine phosphorylated proteins in WT and Itgα1-null kidney cells. We show that the phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is higher in Itgα1-null cells. FUS contains EGFR-targeted phosphorylation sites and, in Itgα1-null cells, activated EGFR promotes FUS phosphorylation and nuclear translocation. Nuclear FUS binds to the collagen IV promoter, commencing gene transcription that is reduced by inhibiting EGFR, down-regulating FUS, or expressing FUS mutated in the EGFR-targeted phosphorylation sites. Finally, a cell-penetrating peptide that inhibits FUS nuclear translocation reduces FUS nuclear content and collagen IV transcription. Thus, EGFR-mediated FUS phosphorylation regulates FUS nuclear translocation and transcription of a major profibrotic collagen gene. Targeting FUS nuclear translocation offers a new antifibrotic therapy.

References

Aug 12, 1999·Acta Neurologica Scandinavica·S OnoN Shimizu
Jul 24, 2001·Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases·S OnoN Shimizu
Dec 31, 2003·The Journal of Biological Chemistry·Ruth Ann VeachJacek Hawiger
Jul 28, 2004·The American Journal of Pathology·Xiwu ChenAmbra Pozzi
Jul 31, 2007·Journal of Cellular Biochemistry·Kelly M QuesnelleJennifer R Grandis
Mar 17, 2010·Human Mutation·Mariely DeJesus-HernandezRosa Rademakers
Jul 8, 2010·The EMBO Journal·Dorothee DormannChristian Haass
Aug 12, 2010·Human Molecular Genetics·Daryl A BoscoLawrence J Hayward
Mar 31, 2012·Proceedings of the National Academy of Sciences of the United States of America·Adelene Y TanJames L Manley
Oct 2, 2012·Nature Neuroscience·Clotilde Lagier-TourenneGene W Yeo
May 3, 2013·Molecular Cancer Research : MCR·Kaiming Xu, Hui-Kuo G Shu
Jul 10, 2013·Antioxidants & Redox Signaling·Sanjit Kumar DharDaret K St Clair
Jul 17, 2013·Experimental Biology and Medicine·Asish K GhoshDouglas E Vaughan
Nov 22, 2013·The Journal of Biological Chemistry·Agnieszka BroniszSudarshana M Sharma
Jun 6, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Qiudong DengThomas Kukar
Jan 8, 2015·Kidney International·Hongtao WangAmbra Pozzi
Jun 4, 2015·Proceedings of the National Academy of Sciences of the United States of America·Tung-Hung SuDing-Shinn Chen
Jul 30, 2015·Neurobiology of Disease·Guinevere F LourencoGlenda M Halliday
Sep 26, 2015·Journal of Cell Science·Simona DarovicBoris Rogelj
May 27, 2016·American Journal of Physiology. Renal Physiology·Fenghua ZengRaymond C Harris
Jun 29, 2016·Cell and Tissue Research·Nuno Miranda Coelho, Christopher A McCulloch
Apr 6, 2017·FEBS Letters·Helena Ederle, Dorothee Dormann
Apr 4, 2018·Nature Structural & Molecular Biology·Feng LuoCong Liu
May 8, 2018·The Journal of Clinical Investigation·Loka R PenkeMarc Peters-Golden
Oct 24, 2018·Scientific Reports·Tadashi Nakaya, Manolis Maragkakis
Jan 24, 2019·Mediators of Inflammation·Sandra Rayego-MateosMarta Ruiz-Ortega
Mar 16, 2019·Scientific Reports·Maria Antonietta Ajmone-CatEmanuele Cacci
Jul 12, 2019·Journal of the American Society of Nephrology : JASN·Ming-Zhi ZhangRaymond C Harris
Aug 6, 2019·Scandinavian Journal of Immunology·Jacek Hawiger, Jozef Zienkiewicz
Aug 7, 2019·Journal of the American Society of Nephrology : JASN·Manuel ChiusaAmbra Pozzi
Sep 22, 2019·Nature Communications·Venkata Naga Srikanth GarikipatiRaj Kishore

❮ Previous
Next ❯

Citations

Dec 29, 2020·American Journal of Physiology. Renal Physiology·Ambra Pozzi, Raymond C Harris
Mar 27, 2021·Current Opinion in Nephrology and Hypertension·Raymond C Harris

❮ Previous
Next ❯

Methods Mentioned

BETA
immunoprecipitation
nuclear translocation
transfections
transfection
ChIP
PCR

Software Mentioned

Phospho Motif Finder
GraphPad Prism
Photoshop
ImageJ
Image Studio Lite
SlideBook

Related Concepts

Related Feeds

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.