Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFβ/BMP signaling in vivo

Conidi, Andrea; Cazzola, Silvia; Beets, Karen; Coddens, Kathleen; Collart, Clara; Cornelis, Frederique; Cox, Luk; Joke, Debruyn; Dobreva, Mariya P.; Dries, Ruben; Esguerra, Camila; Francis, Annick; Ibrahimi, Abdelilah; Kroes, Roel; Lesage, Flore; Maas, Elke; Moya, Ivan; Pereira, Paulo N.G.; Stappers, Elke; Stryjewska, Agata; van den Berghe, Veronique; Vermeire, Liesbeth; Verstappen, Griet; Seuntjens, Eve; Umans, Lieve; Zwijsen, An; Huylebroeck, Danny

doi:10.1016/j.cytogfr.2011.11.006

« Previous Next »Cytokine & Growth Factor Reviews
Volume 22, Issue 5 , Pages 287-300, October 2011

Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFβ/BMP signaling in vivo

Andrea Conidi
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Shared first authors.
- Tel.: +32 16 373135; fax: +32 16 372581.
Silvia Cazzola
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Shared first authors.
- Tel.: +32 16 373137; fax: +32 16 372581.
Karen Beets
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 10 753025; fax: +32 10 753000.
Kathleen Coddens
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373137; fax: +32 16 372581.
Clara Collart
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Present address: Systems Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. Tel.: +44 20 8816 2272; fax: +44 20 8906 4477.
Frederique Cornelis
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Present address: Division of Rheumatology, University of Leuven, Campus Gasthuisberg, Building Ond&Nav1, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 346151; fax: +32 16 346200.
Luk Cox
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Present address: Laboratory of Molecular Pathogenesis of Leukemia of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 330119; fax: +32 16 330084.
Debruyn Joke
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 10 753025; fax: +32 10 753000.
Mariya P. Dobreva
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 330724; fax: +32 16 372581.
Ruben Dries
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373137; fax: +32 16 372581.
Camila Esguerra
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Present address: Laboratory of Pharmaceutical Biology, University of Leuven, Campus Gasthuisberg, Building Ond&Nav2 Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 323439; fax: +32 16 323460.
Annick Francis
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373137; fax: +32 16 372581.
Abdelilah Ibrahimi
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 495 221103; fax: +32 10 753000.
Roel Kroes
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373135; fax: +32 16 372581.
Flore Lesage
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373135; fax: +32 16 372581.
Elke Maas
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373169; fax: +32 16 372581.
Ivan Moya
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 330724; fax: +32 16 372581.
Paulo N.G. Pereira
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 330006; fax: +32 16 372581.
Elke Stappers
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373135; fax: +32 16 372581.
Agata Stryjewska
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373137; fax: +32 16 372581.
Veronique van den Berghe
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373135; fax: +32 16 372581.
Liesbeth Vermeire
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Present address: InfraMouse, Animal facility, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 330757; fax: +32 16 372581.
Griet Verstappen
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373135; fax: +32 16 372581.
Eve Seuntjens
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373135; fax: +32 16 372581.
Lieve Umans
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 373137; fax: +32 16 372581.
An Zwijsen
- Laboratory of Developmental Signaling of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), Campus Gasthuisberg, Building Ond&Nav4 level 06, Herestraat 49, B-3000 Leuven, Belgium
- Tel.: +32 16 330006; fax: +32 16 372581.
Danny Huylebroeck
- Laboratory of Molecular Biology (Celgen) of the Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Department of Molecular and Developmental Genetics (VIB11), University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 level 05, Herestraat 49, B-3000 Leuven, Belgium
- Corresponding author at: Laboratory of Molecular Biology (Celgen), c/o Stem Cell Institute, University of Leuven, Campus Gasthuisberg, Building Ond&Nav4 (room 05.313), Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 373139; fax: +32 16 372581.

published online 28 November 2011.

Abstract

Signaling by the many ligands of the TGFβ family strongly converges towards only five receptor-activated, intracellular Smad proteins, which fall into two classes i.e. Smad2/3 and Smad1/5/8, respectively. These Smads bind to a surprisingly high number of Smad-interacting proteins (SIPs), many of which are transcription factors (TFs) that co-operate in Smad-controlled target gene transcription in a cell type and context specific manner. A combination of functional analyses in vivo as well as in cell cultures and biochemical studies has revealed the enormous versatility of the Smad proteins. Smads and their SIPs regulate diverse molecular and cellular processes and are also directly relevant to development and disease. In this survey, we selected appropriate examples on the BMP-Smads, with emphasis on Smad1 and Smad5, and on a number of SIPs, i.e. the CPSF subunit Smicl, Ttrap (Tdp2) and Sip1 (Zeb2, Zfhx1b) from our own research carried out in three different vertebrate models.

Abbreviations: Alk, activin receptor-like kinase, CPSF, cleavage polyadenylation specificity complex, HD, Hirschsprung disease, MR, mental retardation, PAH, pulmonary arterial hypertension, PD, Parkinson disease, SIP, Smad-interacting protein, Smicl, Smad-interacting CPSF-like protein, Tdp, Tyrosyl DNA phosphodiesterase, TF, transcription factor, Ttrap, TNF receptor and Traf-associated protein