title: Controlling long-term signaling: receptor dynamics determine attenuation and refractory behavior of the TGF-β pathway.
abstract: Understanding the complex dynamics of growth factor signaling requires both mechanistic and kinetic information. Although signaling dynamics have been studied for pathways downstream of receptor tyrosine kinases and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, they have not been investigated for the transforming growth factor-β (TGF-β) superfamily pathways. Using an integrative experimental and mathematical modeling approach, we dissected the dynamic behavior of the TGF-β to Smad pathway, which is mediated by type I and type II receptor serine/threonine kinases, in response to acute, chronic, and repeated ligand stimulations. TGF-β exposure produced a transient response that attenuated over time, resulting in desensitized cells that were refractory to further acute stimulation. This loss of signaling competence depended on ligand binding, but not on receptor activity, and was restored only after the ligand had been depleted. Furthermore, TGF-β binding triggered the rapid depletion of signaling-competent receptors from the cell surface, with the type I and type II receptors exhibiting different degradation and trafficking kinetics. A computational model of TGF-β signal transduction from the membrane to the nucleus that incorporates our experimental findings predicts that autocrine signaling, such as that associated with tumorigenesis, severely compromises the TGF-β response, which we confirmed experimentally. Thus, we have shown that the long-term signaling behavior of the TGF-β pathway is determined by receptor dynamics, does not require TGF-β-induced gene expression, and influences context-dependent responses in vivo.
authors: 1Developmental Signalling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Pedro
authors: P
authors: Vizán
authors: Daniel S J
authors: DS
authors: Miller
authors: Ilaria
authors: I
authors: Gori
authors: Debipriya
authors: D
authors: Das
authors: Bernhard
authors: B
authors: Schmierer
authors: Caroline S
authors: CS
authors: Hill
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II