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Crosstalk of cyclic GMP dependent kinase I and BMP signaling
BMC Pharmacology volume 9, Article number: P23 (2009)
Bone morphogenetic proteins (BMPs) are members of the TGFβ growth factor superfamily and have important roles in proliferation, development, differentiation of embryonic and adult cells, as well as in tissue regeneration. BMPs signal via two transmembrane serine/threonine kinase receptors, the BMP type I (BMPRIa and BMPRIb) and BMP type II (BMPRII) receptors which can form homo- and heterooligomeric complexes. They occur in distinct membrane areas, are differently modulated upon ligand binding and are subsequently endocytosed . Upon ligand binding to the receptor complex a signaling cascade via Smad proteins or independent of Smads is initiated and results in expression of specific target genes.
cGMP-dependent kinase I (cGKI) was identified as a BMPRII interacting protein in a proteomics-based approach using the cytoplasmic BMPRII-tail region as bait . cGKI is a cytoplasmic serine/threonine kinase and signals via the NO/cGMP/cGK pathway and is involved in regulation of growth, differentiation and apoptosis of cells .
The involvement of cGKI in BMP signaling could be validated as it positively influences receptor and Smad activation at the plasma membrane as well as it enhances the transcription of target genes in the nucleus . New results hint towards the fact that cGKI is involved in endocytotic events in BMP signaling, as it dynamically interacts with BMPRII upon BMP-2 stimulation and enhances the internalization of the receptor. Interfering with endocytosis in the cell inhibits BMP signaling mediated by BMP-2 and cGKI.
Clinical evidence for the involvement of cGKI in BMP-signaling is given by the fact that mutations in the BMPRII are related to the development of primary arterial hypertension (PAH) . Patients with PAH suffer from vasoconstriction and elevated pressure in the pulmonary arteries, but the distinct pathway leading to the specific phenotype is still unraveled. We could show that ineffective signaling caused by mutant BMPRII found in PAH could be compensated through cGKI .
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Heining, E., Schwappacher, R., Horbelt, D. et al. Crosstalk of cyclic GMP dependent kinase I and BMP signaling. BMC Pharmacol 9, P23 (2009). https://doi.org/10.1186/1471-2210-9-S1-P23
- Bone Morphogenetic Protein
- Smad Protein
- Specific Target Gene
- Smad Activation
- Distinct Membrane