Novel crosstalk to BMP signalling: cGMP-dependent kinase I modulates BMP receptor and Smad activity.
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.
Institute for Chemistry/Biochemistry, FU Berlin, Berlin, Germany.
Raphaela
R
Schwappacher
Jörg
J
Weiske
Eva
E
Heining
Verena
V
Ezerski
Barak
B
Marom
Yoav I
YI
Henis
Otmar
O
Huber
Petra
P
Knaus
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051785:Smad Proteins / Q000378:metabolism*; D019473:Transcription Factors, TFII; D014158:Transcription, Genetic
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; D019473:Transcription Factors, TFII; D017869:Cyclic GMP-Dependent Protein Kinases; C498218:BMPR2 protein, human; D052004:Bone Morphogenetic Protein Receptors; D052006:Bone Morphogenetic Protein Receptors, Type II