Premium
Receptor expression modulates the specificity of transforming growth factor‐β signaling pathways
Author(s) -
Murakami Masaru,
Kawachi Hiroyuki,
Ogawa Kenji,
Nishino Yoshii,
Funaba Masayuki
Publication year - 2009
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2009.01283.x
Subject(s) - smad , phosphorylation , biology , smad2 protein , acvr2b , signal transduction , microbiology and biotechnology , r smad , receptor , activin type 2 receptors , transforming growth factor beta , kinase , tgf beta signaling pathway , transforming growth factor , biochemistry , growth factor , tgf alpha
In current models of transforming growth factor‐β (TGF‐β) family signaling, type II receptors activate specific activin receptor‐like kinase (ALK) type I receptors. These serine/threonine kinases activate ligand‐dependent receptor regulated (R)‐Smad by phosphorylating carboxy‐terminal serines. We found that the receptor expression levels affected the phosphorylation and activation of the two R‐Smad subclasses, activin/TGF‐β‐specific (AR‐Smad) and bone morphogenetic protein (BMP)‐specific (BR‐Smad). Co‐expressing constitutively active type I and type II receptors in COS7 cells resulted in the phosphorylation of both R‐Smad subclasses in a ligand‐independent manner. This was verified using in vitro kinase assays. In untransfected B16 melanoma cells, TGF‐β1 and BMP‐2 induced phosphorylation of both R‐Smad subclasses, and TGF‐β1 up‐regulated the inhibitor of differentiation ( Id ) gene, which is usually regulated by BMP. By contrast, BMP‐2 up‐regulated plasminogen activator inhibitor‐1 (PAI‐1), which is an AR‐Smad‐regulated gene. Except for ALK4 and ALK6, levels of type I and type II receptor mRNAs were higher in B16 cells than in HeLa and HepG2 cells, in which TGF‐β1 and BMP‐2 induced phosphorylation of only the expected R‐Smad. These results help to explain the diverse effects of this ligand family.