Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.
- MeSH
- aktivinové receptory typu I antagonisté a inhibitory metabolismus MeSH
- aktivinové receptory typu II * metabolismus antagonisté a inhibitory MeSH
- inhibitory proteinkinas farmakologie chemie MeSH
- kostní morfogenetické proteiny metabolismus MeSH
- lidé MeSH
- molekulární sondy chemie MeSH
- myši MeSH
- objevování léků MeSH
- pyrazoly chemie farmakologie chemická syntéza MeSH
- signální transdukce účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aktivinové receptory typu I MeSH
- aktivinové receptory typu II * MeSH
- inhibitory proteinkinas MeSH
- kostní morfogenetické proteiny MeSH
- molekulární sondy MeSH
- pyrazoly MeSH
The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.
- Klíčová slova
- FGFR, biased signaling, molecular biophysics, none, signal transduction, structural biology,
- MeSH
- fibroblastové růstové faktory * MeSH
- fosforylace MeSH
- lidé MeSH
- ligandy MeSH
- receptor fibroblastových růstových faktorů, typ 1 genetika MeSH
- signální transdukce * MeSH
- těhotenství MeSH
- zkreslení výsledků (epidemiologie) MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- FGFR1 protein, human MeSH Prohlížeč
- fibroblastové růstové faktory * MeSH
- ligandy MeSH
- receptor fibroblastových růstových faktorů, typ 1 MeSH
