Article
- The EMBO Journal (2009) 28, 1537 - 1550
- doi:10.1038/emboj.2009.103
Published online: 7 May 2009
Subject Category:
Novel crosstalk to BMP signalling: cGMP-dependent kinase I modulates BMP receptor and Smad activity
Raphaela Schwappacher1, Jörg Weiske2, Eva Heining1, Verena Ezerski1, Barak Marom3, Yoav I Henis3, Otmar Huber2,4 and Petra Knaus1
- Institute for Chemistry/Biochemistry, FU Berlin, Berlin, Germany
- Department of Laboratory Medicine and Pathobiochemistry, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Department of Neurobiology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
- Institute for Biochemistry, Friedrich Schiller University, Jena, Germany
Correspondence to:
Petra Knaus, Institute for Chemistry/Biochemistry, FU Berlin, Thielallee 63, 14195 Berlin, Germany. Tel.: +49 30 838 52935; Fax: +49 30 838 51935; E-mail: knaus@chemie.fu-berlin.de
Received 8 October 2008; Accepted 20 March 2009
Abstract
Integration of multiple signals into the canonical BMP/Smad pathway poses a big challenge during the course of embryogenesis and tissue homeostasis. Here, we show that cyclic guanosine 3',5'-monophosphate (cGMP)-dependent kinase I (cGKI) modulates BMP receptors and Smads, providing a novel mechanism enhancing BMP signalling. cGKI, a key mediator of vasodilation and hypertension diseases, interacts with and phosphorylates the BMP type II receptor (BMPRII). In response to BMP-2, cGKI then dissociates from the receptors, associates with activated Smads, and undergoes nuclear translocation. In the nucleus, cGKI binds with Smad1 and the general transcription factor TFII-I to promoters of BMP target genes such as Id1 to enhance transcriptional activation. Accordingly, cGKI has a dual function in BMP signalling: (1) it modulates BMP receptor/Smad activity at the plasma membrane and (2) after redistribution to the nucleus, it further regulates transcription as a nuclear co-factor for Smads. Consequently, cellular defects caused by mutations in BMPRII, found in pulmonary arterial hypertension patients, were compensated through cGKI, supporting the positive action of cGKI on BMP-induced Smad signalling downstream of the receptors.
Keywords:
- bone morphogenetic protein,
- cGMP-dependent protein kinase,
- pulmonary arterial hypertension,
- Smad,
- TFII-I
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