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Novel crosstalk to BMP signalling: cGMP‐dependent kinase I modulates BMP receptor and Smad activity
Author(s) -
Schwappacher Raphaela,
Weiske Jörg,
Heining Eva,
Ezerski Verena,
Marom Barak,
Henis Yoav I,
Huber Otmar,
Knaus Petra
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.103
Subject(s) - biology , crosstalk , smad , microbiology and biotechnology , bone morphogenetic protein , signalling , bmpr2 , smad2 protein , bone morphogenetic protein 2 , signal transduction , kinase , biochemistry , gene , physics , optics , in vitro
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.