The Shp2-induced epithelial disorganization defect is reversed by HDAC6 inhibition independent of Cdc42

Nature Communications
Sui-Chih TienZee-Fen Chang

Abstract

Regulation of Shp2, a tyrosine phosphatase, critically influences the development of various diseases. Its role in epithelial lumenogenesis is not clear. Here we show that oncogenic Shp2 dephosphorylates Tuba to decrease Cdc42 activation, leading to the abnormal multi-lumen formation of epithelial cells. HDAC6 suppression reverses oncogenic Shp2-induced multiple apical domains and spindle mis-orientation during division in cysts to acquire normal lumenogenesis. Intriguingly, Cdc42 activity is not restored in this rescued process. We present evidence that simultaneous reduction in myosin II and ERK1/2 activity by HDAC6 inhibition is responsible for the reversion. In HER2-positive breast cancer cells, Shp2 also mediates Cdc42 repression, and HDAC6 inhibition or co-suppression of ERK/myosin II promotes normal epithelial lumen phenotype without increasing Cdc42 activity. Our data suggest a mechanism of epithelial disorganization by Shp2 deregulation, and reveal the cellular context where HDAC6 suppression is capable of establishing normal epithelial lumenogenesis independent of Cdc42.

References

Aug 23, 1996·The Journal of Biological Chemistry·M AmanoK Kaibuchi
Mar 10, 1998·Cell·P HofS E Shoelson
Jul 11, 1998·The Journal of Biological Chemistry·M F FavataJ M Trzaskos
May 25, 2002·Nature·Charlotte HubbertTso-Pang Yao
Apr 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Stephen J HaggartyStuart L Schreiber
Jun 27, 2003·Trends in Biochemical Sciences·Benjamin G NeelLily Pao
Dec 17, 2005·American Journal of Human Genetics·Marco TartagliaBruce D Gelb
Dec 22, 2005·Nature Medicine·Mohamed Bentires-AljHaihua Gu
Jan 18, 2006·Methods in Enzymology·Gianluca CestraPietro De Camilli
Feb 14, 2006·Methods in Enzymology·Rafael García-MataKeith Burridge
Mar 7, 2006·Developmental Cell·Wentian YangBenjamin G Neel
Jan 18, 2007·Current Opinion in Genetics & Development·M Golam Mohi, Benjamin G Neel
Nov 6, 2007·Developmental Cell·Bob Goldstein, Ian G Macara
Jan 9, 2008·Molecular and Cellular Biology·Yu ZhangPatrick Matthias
Apr 19, 2008·Cell Death and Differentiation·X-D Zhou, Y M Agazie
Jun 19, 2008·The Journal of Cell Biology·Hsiao-Hui Lee, Zee-Fen Chang
Nov 20, 2008·Proceedings of the National Academy of Sciences of the United States of America·Maike KrenzJeffrey Robbins
Mar 6, 2009·The Journal of Biological Chemistry·Xiangdong Zhou, Yehenew M Agazie
Dec 1, 2009·Cell·Jean Paul ThieryM Angela Nieto
Oct 5, 2010·Nature Cell Biology·David M BryantKeith E Mostov
Feb 9, 2011·Current Biology : CB·Anirban DattaKeith E Mostov
Feb 9, 2011·The Journal of Biological Chemistry·Joanne DurganAlan Hall
May 18, 2011·Cancer Cell·Emilie A Bard-ChapeauGen-Sheng Feng
Jan 26, 2012·The Biochemical Journal·Hsiang-Hao ChuangHsiao-Hui Lee
Mar 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Audrey De Rocca Serra-NédélecArmelle Yart
Sep 12, 2012·The Journal of Cell Biology·Alejo E Rodríguez-FraticelliFernando Martín-Belmonte
Nov 17, 2012·Cancer Cell·Luke Martin McCaffreyIan G Macara
Dec 1, 2012·Nature Cell Biology·Gerard ApodacaDavid M Bryant
Mar 21, 2013·Small GTPases·Alejo E Rodríguez-Fraticelli, Fernando Martín-Belmonte

❮ Previous
Next ❯

Citations

Aug 14, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jie ZhangYuehai Ke
Nov 9, 2017·Oncotarget·Teru HideshimaKenneth C Anderson
Aug 3, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kedar GhimireNatasha M Rogers

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPase
acetylation
transfection
pull-down
Assay

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.