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Gene expression profiling demonstrates that TGF-ß1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-ß signaling

¹ Department of Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund, Sweden
² The Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden
³ Complex Systems Division, Department of Theoretical Physics, Lund University, Lund, Sweden
⁴ Department of Cardiology, Heart Lung Center, Utrecht, the Netherlands
⁵ Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland

Transforming growth factor-ß1 (TGF-ß) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-ß binds to receptor complexes consisting of TGF-ß receptor type II (TßRII) 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 TßRII/Alk5 can be relevant for TGF-ß signaling. We have screened for alternative receptors for TGF-ß and also for gene targets of TGF-ß signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-ß-stimulated Alk5^–/– cells show them to be completely unaffected by TGF-ß. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5^–/– or TGF-ß-stimulated Alk5^+/+ MEFs with unstimulated Alk5^+/+ cells. Our results demonstrate that, in MEFs, TGF-ß signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.

signal transduction; Smad; microarrays

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