Novel crosstalk to BMP signalling: cGMP-dependent kinase I modulates BMP receptor and Smad activity

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.

Signaling Receptors for TGF-β Family Members

“…The cyclic guanosine 3 0 ,5 0 -monophosphate-dependent kinase I (cGKI) associates with and phosphorylates the BMPRII cytoplasmic domain (Schwappacher et al 2009). On BMPRII activation by ligand binding, cGKI dissociates from the receptor and translocates to the nucleus bound to Smad1, assisting in transcriptional regulation by the Smad complex.…”

Sildenafil Potentiates Bone Morphogenetic Protein Signaling in Pulmonary Arterial Smooth Muscle Cells and in Experimental Pulmonary Hypertension

“…It is widely used as an effective treatment for clinical PAH. 9 Recently, Schwappacher et al 10 reported that cGMP-dependent kinase I (cGKI) modulates BMP signaling in a mouse myoblast cell line. These authors found that cGKI interacts with BMPR-II, and that on BMP stimulation, cGKI is released to associate with activated Smad proteins and regulates gene expression as a nuclear cofactor for Smads.…”

Association of BMP6 Methylation and Expression with Clinicopathological Features in Colorectal Cancer

“…Like other BMP family members, BMP6 accessibility is modulated by specific antagonists. Receptor activation is controlled by co-receptors, by localization to distinct membrane microdomains, by endocytosis and by receptor associated proteins [38][39][40]. Approximately 40 TGF-β superfamily ligands differentially bind and signal through only 12 common receptors indicating that each receptor has multiple ligand-binding partners.…”