TGF-beta receptor levels regulate the specificity of signaling pathway activation and biological effects of TGF-beta.
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.
Rojas
Andres
A
Clinical Research Division, Fred Hutchinson Cancer Research Center, WA 98109, USA.
Padidam
Malla
M
Cress
Dean
D
Grady
William M
WM