Human Molecular Genetics Advance Access published online on October 28, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg365
© 2003 by Oxford University Press
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1 Division of Medical Genetics, University of Leicester LE1 7RH, UK
Diverse heterozygous mutations of bone morphogenetic receptor type II (BMPR-II) underlie the inherited form of the vascular disorder primary pulmonary hypertension (PPH). As yet, the molecular detail of how such defects contribute to the pathogenesis of PPH remains unclear. BMPR-II is a member of the transforming growth factor-
Article
Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform specific and disrupted by mutations underlying Primary Pulmonary Hypertension
2 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge CB2 2QQ, UK
3 Division of Medical Genetics, Department of Genetics and Medicine, Adrian Building, University Road, Leicester LE1 7RH, UK
Abstract 
cell signalling superfamily. Ligand binding induces cell surface receptor complex formation and activates a cascade of phosphorylation events of intracellular intermediaries termed Smads, which initiate transcriptional regulation. Some 30% of PPH causing mutations localise to exon 12, which may be spliced out forming an isoform depleted of the unusually long BMPR-II cytoplasmic tail. To further elucidate the consequences of BMPR2 mutation, we sought to characterise aspects of the cytoplasmic domain function, by seeking intracellular binding partners. We now report that Tctex-1, a light chain of the motor complex dynein, interacts with the cytoplasmic domain of BMPR-II and demonstrate that Tctex-1 is phosphorylated by BMPR-II, a function disrupted by PPH disease causing mutations within exon 12. Finally we show that BMPR-II and Tctex-1 co-localise to endothelium and smooth muscle within the media of pulmonary arterioles, key sites of vascular remodelling in PPH. Taken together, these data demonstrate a discrete function for the cytoplasmic domain of BMPR-II and justifies further investigation of whether the interaction with and phosphorylation of Tctex-1 contributes to the pathogenesis of PPH.
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