TGF-beta receptor levels regulate the specificity of signaling pathway activation and biological effects of TGF-beta

Biochim Biophys Acta. 2009 Jul;1793(7):1165-73. doi: 10.1016/j.bbamcr.2009.02.001. Epub 2009 Feb 12.

Abstract

TGF-beta is a pluripotent cytokine that mediates its effects through a receptor composed of TGF-beta receptor type II (TGFBR2) and type I (TGFBR1). The TGF-beta receptor can regulate Smad and nonSmad signaling pathways, which then ultimately dictate TGF-beta's biological effects. We postulated that control of the level of TGFBR2 is a mechanism for regulating the specificity of TGF-beta signaling pathway activation and TGF-beta's biological effects. We used a precisely regulatable TGFBR2 expression system to assess the effects of TGFBR2 expression levels on signaling and TGF-beta mediated apoptosis. We found Smad signaling and MAPK-ERK signaling activation levels correlate directly with TGFBR2 expression levels. Furthermore, p21 levels and TGF-beta induced apoptosis appear to depend on relatively high TGFBR2 expression and on the activation of the MAPK-ERK and Smad pathways. Thus, control of TGFBR2 expression and the differential activation of TGF-beta signaling pathways appears to be a mechanism for regulating the specificity of the biological effects of TGF-beta.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Cells, Cultured
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Luciferases / metabolism
  • MAP Kinase Signaling System
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Smad7 Protein
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Smad7 Protein
  • Transforming Growth Factor beta
  • Luciferases
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR1 protein, human