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Receptor for activated C-kinase 1, a novel interaction partner of type II bone morphogenetic protein receptor, regulates smooth muscle cell proliferation in pulmonary arterial hypertension.
Circulation. 2007 Jun 12; 115(23):2957-68.Circ

Abstract

BACKGROUND

Pulmonary arterial hypertension (PAH) is characterized by selective elevation of pulmonary arterial pressure. The pathological hallmark of PAH is the narrowing of pulmonary arterioles secondary to endothelial cell dysfunction and smooth muscle cell proliferation. Heterozygous mutations in BMPR2, encoding the type II bone morphogenetic protein receptor (BMPRII), were identified in PAH, suggesting that alterations to BMPRII function are involved in disease onset and/or progression.

METHODS AND RESULTS

We identified the receptor for activated C-kinase (RACK1) as a novel interaction partner of BMPRII by yeast 2-hybrid analyses using the kinase domain of BMPRII as a bait. Glutathione-S-transferase pull-down and coimmunoprecipitation confirmed the interaction of RACK1 with BMPRII in vitro and in vivo. RACK1-BMPRII interaction was reduced when kinase domain mutations occurring in patients with PAH were introduced to BMPRII. Immunohistochemistry of lung sections from PAH and control patients and immunofluorescence analysis of primary pulmonary arterial smooth muscle cells demonstrated colocalization of BMPRII and RACK1 in vivo. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis showed significant downregulation of RACK1 expression in the rat model of monocrotaline-induced PAH but not in pulmonary arterial smooth muscle cells from PAH patients. Abrogation of RACK1 expression in pulmonary arterial smooth muscle cells led to decreased Smad1 phosphorylation and increased proliferation, whereas overexpression of RACK1 led to increased Smad1 phosphorylation and decreased proliferation.

CONCLUSIONS

RACK1, a novel interaction partner of BMPRII, constitutes a new negative regulator of pulmonary arterial smooth muscle cell proliferation, suggesting a potential role for RACK1 in the pathogenesis of PAH.

Authors+Show Affiliations

University of Giessen Lung Center, Department of Medicine II, Justus Liebig University Giessen, D-35392 Giessen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17515463

Citation

Zakrzewicz, Anna, et al. "Receptor for Activated C-kinase 1, a Novel Interaction Partner of Type II Bone Morphogenetic Protein Receptor, Regulates Smooth Muscle Cell Proliferation in Pulmonary Arterial Hypertension." Circulation, vol. 115, no. 23, 2007, pp. 2957-68.
Zakrzewicz A, Hecker M, Marsh LM, et al. Receptor for activated C-kinase 1, a novel interaction partner of type II bone morphogenetic protein receptor, regulates smooth muscle cell proliferation in pulmonary arterial hypertension. Circulation. 2007;115(23):2957-68.
Zakrzewicz, A., Hecker, M., Marsh, L. M., Kwapiszewska, G., Nejman, B., Long, L., Seeger, W., Schermuly, R. T., Morrell, N. W., Morty, R. E., & Eickelberg, O. (2007). Receptor for activated C-kinase 1, a novel interaction partner of type II bone morphogenetic protein receptor, regulates smooth muscle cell proliferation in pulmonary arterial hypertension. Circulation, 115(23), 2957-68.
Zakrzewicz A, et al. Receptor for Activated C-kinase 1, a Novel Interaction Partner of Type II Bone Morphogenetic Protein Receptor, Regulates Smooth Muscle Cell Proliferation in Pulmonary Arterial Hypertension. Circulation. 2007 Jun 12;115(23):2957-68. PubMed PMID: 17515463.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Receptor for activated C-kinase 1, a novel interaction partner of type II bone morphogenetic protein receptor, regulates smooth muscle cell proliferation in pulmonary arterial hypertension. AU - Zakrzewicz,Anna, AU - Hecker,Matthias, AU - Marsh,Leigh M, AU - Kwapiszewska,Grazyna, AU - Nejman,Bozena, AU - Long,Lu, AU - Seeger,Werner, AU - Schermuly,Ralph T, AU - Morrell,Nicholas W, AU - Morty,Rory E, AU - Eickelberg,Oliver, Y1 - 2007/05/21/ PY - 2007/5/23/pubmed PY - 2007/7/4/medline PY - 2007/5/23/entrez SP - 2957 EP - 68 JF - Circulation JO - Circulation VL - 115 IS - 23 N2 - BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by selective elevation of pulmonary arterial pressure. The pathological hallmark of PAH is the narrowing of pulmonary arterioles secondary to endothelial cell dysfunction and smooth muscle cell proliferation. Heterozygous mutations in BMPR2, encoding the type II bone morphogenetic protein receptor (BMPRII), were identified in PAH, suggesting that alterations to BMPRII function are involved in disease onset and/or progression. METHODS AND RESULTS: We identified the receptor for activated C-kinase (RACK1) as a novel interaction partner of BMPRII by yeast 2-hybrid analyses using the kinase domain of BMPRII as a bait. Glutathione-S-transferase pull-down and coimmunoprecipitation confirmed the interaction of RACK1 with BMPRII in vitro and in vivo. RACK1-BMPRII interaction was reduced when kinase domain mutations occurring in patients with PAH were introduced to BMPRII. Immunohistochemistry of lung sections from PAH and control patients and immunofluorescence analysis of primary pulmonary arterial smooth muscle cells demonstrated colocalization of BMPRII and RACK1 in vivo. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis showed significant downregulation of RACK1 expression in the rat model of monocrotaline-induced PAH but not in pulmonary arterial smooth muscle cells from PAH patients. Abrogation of RACK1 expression in pulmonary arterial smooth muscle cells led to decreased Smad1 phosphorylation and increased proliferation, whereas overexpression of RACK1 led to increased Smad1 phosphorylation and decreased proliferation. CONCLUSIONS: RACK1, a novel interaction partner of BMPRII, constitutes a new negative regulator of pulmonary arterial smooth muscle cell proliferation, suggesting a potential role for RACK1 in the pathogenesis of PAH. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/17515463/Receptor_for_activated_C_kinase_1_a_novel_interaction_partner_of_type_II_bone_morphogenetic_protein_receptor_regulates_smooth_muscle_cell_proliferation_in_pulmonary_arterial_hypertension_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.106.670026?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -