Probing the role of homomeric and heteromeric receptor interactions in TGF-beta signaling using small molecule dimerizers

Curr Biol. 1998 Jun 18;8(13):761-70. doi: 10.1016/s0960-9822(98)70299-4.


Background: Transforming growth factor Beta (TGF-Beta) arrests many cell types in the G1 phase of the cell and upregulates plasminogen activator inhibitor 1 (PAI-1). The type 1 (TGF-Beta RI) an II (TGF-Beta RII) TGF-Beta receptors mediate these and other effects of TGF-Beta on target cells. TGF-Beta initially binds to TGF-Beta RII and subsequently TGF-Beta RI is recruited to form a heteromeric complex. TGF-Beta RI phosphorylates the downstream effectors Smad2 and Smad3, leading to their translocation into the nucleus. Here, we explored the role of receptor oligomerization in TGF-Beta signaling.

Results: We constructed fusion proteins containing receptor cytoplasmic tails linked to binding domains for small-molecule dimerizers. In COS-1 cells, recruitment of a soluble TGF-Beta RII tail to a myristoylated TGF-Beta RI tail promoted Smad2 nuclear translocation. In mink lung cells, homo-oligomerization of a myristoylated TGF-Beta Ri tail in presence of a myristoylated TGF-Beta RII tail activated the PAI-1 promoter. Oligomerization of an acidic mutant of the TGF-Beta RI tail in absence of TGF-Beta RII activated the PAI-A promoter and inhibited the growth of mink lung cells.

Conclusions: Non-toxic, small molecules designed to oligomerize cytoplasmic tails of TGF-Beta receptors at the plasma membrane can activate TGF-Beta signaling. Although TGF-Beta normally signals through two receptors that are both necessary for signaling, in one small-molecule system, a dimerizer activates signaling through a single type of receptor that is sufficient to induce TGF-Beta signaling. These methods of activating TGF-Beta signaling could be extended to signaling pathways of other TGF-Beta superfamily members such as activin and the bone morphogenetic proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activin Receptors, Type I*
  • Animals
  • COS Cells
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Green Fluorescent Proteins
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Molecular Probes / metabolism*
  • Myristates / metabolism
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / physiology*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / metabolism
  • Receptors, Transforming Growth Factor beta / physiology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology*
  • Smad2 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / physiology*


  • DNA-Binding Proteins
  • Luminescent Proteins
  • Molecular Probes
  • Myristates
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Green Fluorescent Proteins
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II