Gene expression profiling demonstrates that TGF-beta1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-beta signaling

Abstract

Transforming growth factor-beta1 (TGF-beta) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-beta binds to receptor complexes consisting of TGF-beta receptor type II (TbetaRII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of TbetaRII/Alk5 can be relevant for TGF-beta signaling. We have screened for alternative receptors for TGF-beta and also for gene targets of TGF-beta signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-beta-stimulated Alk5(-/-) cells show them to be completely unaffected by TGF-beta. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5(-/-) or TGF-beta-stimulated Alk5(+/+) MEFs with unstimulated Alk5(+/+) cells. Our results demonstrate that, in MEFs, TGF-beta signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.