Ubiquitin-specific protease 4 inhibits mono-ubiquitination of the master growth factor signaling kinase PDK1.

PloS One
Iris Z UrasSebastian M B Nijman

Abstract

Phosphorylation by the phospho-inositide-dependent kinase 1 (PDK1) is essential for many growth factor-activated kinases and thus plays a critical role in various processes such as cell proliferation and metabolism. However, the mechanisms that control PDK1 have not been fully explored and this is of great importance as interfering with PDK1 signaling may be useful to treat diseases, including cancer and diabetes. In human cells, few mono-ubiquitinated proteins have been described but in all cases this post-translational modification has a key regulatory function. Unexpectedly, we find that PDK1 is mono-ubiquitinated in a variety of human cell lines, indicating that PDK1 ubiquitination is a common and regulated process. Ubiquitination occurs in the kinase domain of PDK1 yet is independent of its kinase activity. By screening a library of ubiquitin proteases, we further identify the Ubiquitin-Specific Protease 4 (USP4) as an enzyme that removes ubiquitin from PDK1 in vivo and in vitro and co-localizes with PDK1 at the plasma membrane when the two proteins are overexpressed, indicating direct deubiquitination. The regulated mono-ubiquitination of PDK1 provides an unanticipated layer of complexity in this central signaling network...Continue Reading

References

Jul 1, 1997·Trends in Biochemical Sciences·B VanhaesebroeckM D Waterfield
Oct 6, 1998·Annual Review of Biochemistry·A Hershko, A Ciechanover
Jun 8, 2001·Annual Review of Biochemistry·C M Pickart
Jun 1, 2002·Science·Lewis C Cantley
Mar 22, 2003·Current Opinion in Cell Biology·Rubén Claudio Aguilar, Beverly Wendland
Jul 16, 2003·Cell·Benoit I Giasson, Virginia M-Y Lee
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Mei A LimLily Q Dong
Mar 17, 2004·Biochimica Et Biophysica Acta·Masahito HanadaBrian A Hemmings
Apr 30, 2004·The EMBO Journal·Edward J McManusDario R Alessi
Jun 24, 2004·Seminars in Cell & Developmental Biology·Alfonso MoraDario R Alessi
Jun 24, 2004·Seminars in Cell & Developmental Biology·Julian Downward
Oct 1, 2004·The EMBO Journal·David KomanderDaan M F van Aalten
Mar 4, 2005·Molecular and Cellular Biology·Michael P ScheidJames R Woodgett
Dec 6, 2005·Cell·Sebastian M B NijmanRené Bernards
Dec 13, 2005·Molecular Pharmacology·Tetyana MilojevicChristian Nanoff
Feb 1, 2006·Molecular Cancer Research : MCR·Wan Mui ChanRandy Y C Poon
Apr 25, 2006·Nature Reviews. Molecular Cell Biology·Tony T Huang, Alan D D'Andrea
Jul 19, 2006·Nature Reviews. Genetics·Jeffrey A EngelmanLewis C Cantley
Jan 16, 2007·Cell·Xinjiang WangXuejun Jiang
Jan 16, 2007·Cell·Lloyd C TrotmanPier Paolo Pandolfi
Jan 16, 2007·Science·Debdyuti Mukhopadhyay, Howard Riezman
Mar 19, 2008·Molecular and Cellular Biology·Jose R BayascasDario R Alessi
Feb 17, 2009·Molecular Cell·Zhijian J Chen, Lijun J Sun
Mar 28, 2009·Nature·Vijay G Bhoj, Zhijian J Chen
Mar 28, 2009·Nature·Daniela Hoeller, Ivan Dikic
Mar 28, 2009·Nature·Camilla Raiborg, Harald Stenmark
Aug 29, 2009·Science·Wei-Lei YangHui-Kuan Lin
Dec 23, 2009·Nature Reviews. Molecular Cell Biology·Laura R PearceDario R Alessi
Feb 10, 2010·Journal of Cellular and Molecular Medicine·Bin ZhaoKristina Lindsten
Mar 20, 2010·Nature Reviews. Cancer·Carlos López-Otín, Tony Hunter
Sep 11, 2010·Nature·Byung-Hoon LeeDaniel Finley
Nov 30, 2010·Cell·Philip Cohen, Marianna Tcherpakov
Feb 19, 2011·Cell Death and Differentiation·Y-H FanJ Yang
Apr 28, 2011·The EMBO Journal·Xinna ZhangXiongbin Lu

❮ Previous
Next ❯

Citations

Apr 25, 2013·Reproduction : the Official Journal of the Society for the Study of Fertility·D K GardnerM G Katz-Jaffe
May 29, 2013·Cell Biochemistry and Biophysics·Xavier JacqStephen P Jackson
Feb 3, 2016·Scientific Reports·Caitlyn VlasschaertDouglas A Gray
Oct 2, 2012·Biochemical and Biophysical Research Communications·Bin ZhaoKristina Lindsten
Jan 22, 2015·Endocrine-related Cancer·Roland PfohVivian Saridakis
Sep 20, 2019·Journal of Experimental & Clinical Cancer Research : CR·Jian-Xian LinPing Li
Jul 20, 2016·International Journal of Molecular Medicine·Yang LiZhengang Cai
Jul 17, 2020·Cancer Cell International·Yizhi WangJunchao Guo
Oct 3, 2020·Molecular Cancer·Tianshui SunQing Yang
Mar 9, 2021·Frontiers in Cell and Developmental Biology·Binbin HuXuelei Ma
Jun 29, 2021·Frontiers in Pharmacology·Yanfeng Wang, Feng Wang

❮ Previous
Next ❯

Methods Mentioned

BETA
ubiquitination
pull-down
immunoprecipitation
transfection
confocal microscopy
mono-ubiquitination
pull-downs
PCR
deubiquitination

Software Mentioned

LAS AF

Related Concepts

Related Feeds

Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.