PMID: 9662508Jul 15, 1998Paper

TGF-beta-signaling with small molecule FKBP12 antagonists that bind myristoylated FKBP12-TGF-beta type I receptor fusion proteins

Chemistry & Biology
B R Stockwell, S L Schreiber

Abstract

Growth arrest in many cell types is triggered by transforming growth factor beta (TGF-beta), which signals through two TGF-beta receptors (type I, TGF-beta RI, and type II, TGF-beta). In the signaling pathway, TGF-beta binds to the extracellular domain of TGF-betaRII, which can then transphosphorylate TGF-betaRI in its glycine/serine (GS)-rich box. Activated TGF-betaRI phosphorylates two downstream effectors, Smad2 and Smad3, leading to their translocation into the nucleus. Cell growth is arrested and plasminogen activator inhibitor 1 (PAI-1) is upregulated. We investigated the role of the immunophilin FKBP12, which can bind to the GS box of TGF-betaRI, in TGF-beta signaling. Overexpression of myristoylated TGF-betaRI and TGF-betaRII cytoplasmic tails caused constitutive nuclear translocation of a green-fluorescent-protein-Smad2 construct in COS-1 cells, and constitutive activation of a PAI-1 reporter plasmid in mink lung cells. Fusing FKBP12 to TGF-betaRI resulted in repression of autosignaling that could be alleviated by FK506M or rapamycin (two small molecules that can bind to FKBP12). Mutation of the FKBP12-binding site in the FKBP1-TGF-betaRI fusion protein restored constitutive signaling. An acidic mutation in the FKBP12-...Continue Reading

References

Jun 1, 1995·Current Opinion in Structural Biology·N W Isaacs
Nov 12, 1993·Science·D M SpencerG R Crabtree
Aug 4, 1994·Nature·J L WranaJ Massagué
May 14, 1996·Proceedings of the National Academy of Sciences of the United States of America·P J BelshawS L Schreiber
Sep 20, 1996·The Journal of Biological Chemistry·M J CharngM D Schneider
Dec 1, 1996·Cytokine & Growth Factor Reviews·L Attisano, J L Wrana
Jul 1, 1997·The EMBO Journal·Y G ChenJ Massague
Aug 19, 1997·Proceedings of the National Academy of Sciences of the United States of America·J N TopperD Falb
Oct 6, 1997·The EMBO Journal·A NakaoP ten Dijke
Oct 23, 1997·Nature·T ImamuraK Miyazono
Oct 6, 1997·Proceedings of the National Academy of Sciences of the United States of America·X LiuH F Lodish

❮ Previous
Next ❯

Citations

Oct 24, 1998·Bioorganic & Medicinal Chemistry·S L Schreiber
Jan 28, 2003·Drug Discovery Today·Kevan Shokat, Mark Velleca
Oct 28, 2008·The Journal of Biological Chemistry·Qian ChenYan Chen
Jun 21, 2008·Molecular Cancer Therapeutics·Jorge A Garcia, David Danielpour
Jun 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Matthew R PrattTom W Muir
Aug 15, 2000·Annual Review of Biophysics and Biomolecular Structure·A BishopK M Shokat
Jun 11, 2003·The Journal of Cell Biology·Prithi RajanRonald D G McKay
Jan 26, 2008·Organic & Biomolecular Chemistry·Mathieu Pucheault
May 16, 2012·FEBS Letters·Mateusz Putyrski, Carsten Schultz
Dec 31, 2004·Cell Research·Ye Guang Chen, An Ming Meng
Dec 20, 2005·The EMBO Journal·Kyung SongDavid Danielpour
Aug 21, 2013·Expert Opinion on Therapeutic Patents·Fei LiuRuo-Yun Tan
Jan 30, 2018·Expert Opinion on Drug Discovery·Mireia Rosell, Juan Fernández-Recio
Sep 26, 2001·The Journal of Biological Chemistry·C GruendlerT Wang
Dec 21, 2018·Frontiers in Pharmacology·Jürgen M KolosFelix Hausch
Feb 22, 2002·The Journal of Biological Chemistry·Erik B FriedrichRobert E Gerszten
Nov 13, 2001·Molecular Cell Biology Research Communications : MCBRC·H J Zhu, A W Burgess
Feb 14, 2002·Chemistry & Biology·Paul A ClemonsStuart L Schreiber
Jul 11, 2006·Cellular Signalling·Constance E RunyanH William Schnaper
Jun 15, 2006·Chemical Reviews·Daniel P Walsh, Young-Tae Chang
Jul 18, 2001·Journal of the American Chemical Society·K KoideG L Verdine

❮ Previous
Next ❯

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.