Human Molecular Genetics Advance Access originally published online on October 28, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, No. 24 3277-3286
DOI: 10.1093/hmg/ddg365
© 2003 Oxford University Press
Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension
1Division of Medical Genetics, University of Leicester, Leicester LE1 7RH, UK and 2Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge CB2 2QQ, UK
Received July 13, 2003; Revised October 8, 2003; Accepted October 17, 2003
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-ß 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 localize 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 characterize 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-localize 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 justify further investigation of whether the interaction with and phosphorylation of Tctex-1 contributes to the pathogenesis of PPH.
* To whom correspondence should be addressed at: Division of Medical Genetics, Department of Genetics and Medicine, Adrian Building, University Road, Leicester LE1 7RH, UK. Tel: +44 1162522269; Fax: +44 116 2523378; Email: rtrembat@hgmp.mrc.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. D. Machado, O. Eickelberg, C. G. Elliott, M. W. Geraci, M. Hanaoka, J. E. Loyd, J. H. Newman, J. A. Phillips III, F. Soubrier, R. C. Trembath, et al. Genetics and Genomics of Pulmonary Arterial Hypertension J. Am. Coll. Cardiol., June 30, 2009; 54(1_Suppl_S): S32 - S42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. de Jesus Perez, T.-P. Alastalo, J. C. Wu, J. D. Axelrod, J. P. Cooke, M. Amieva, and M. Rabinovitch Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-{beta}-catenin and Wnt-RhoA-Rac1 pathways J. Cell Biol., January 12, 2009; 184(1): 83 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. West, J. Harral, K. Lane, Y. Deng, B. Ickes, D. Crona, S. Albu, D. Stewart, and K. Fagan Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L744 - L755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Khan, M. S. Nelson, C. Pan, P. M. Gaffney, and P. Gupta Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1387 - C1397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. B. Yu, D. Y. Deng, H. Beppu, C. C. Hong, C. Lai, S. A. Hoyng, N. Kawai, and K. D. Bloch Bone Morphogenetic Protein (BMP) Type II Receptor Is Required for BMP-mediated Growth Arrest and Differentiation in Pulmonary Artery Smooth Muscle Cells J. Biol. Chem., February 15, 2008; 283(7): 3877 - 3888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Ramos, M. W. Lame, H. J. Segall, and D. W. Wilson Smad Signaling in the Rat Model of Monocrotaline Pulmonary Hypertension Toxicol Pathol, February 1, 2008; 36(2): 311 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lagna, M. M. Ku, P. H. Nguyen, N. A. Neuman, B. N. Davis, and A. Hata Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors J. Biol. Chem., December 21, 2007; 282(51): 37244 - 37255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Chan, P. H. Nguyen, B. N. Davis, N. Ohoka, H. Hayashi, K. Du, G. Lagna, and A. Hata A Novel Regulatory Mechanism of the Bone Morphogenetic Protein (BMP) Signaling Pathway Involving the Carboxyl-Terminal Tail Domain of BMP Type II Receptor Mol. Cell. Biol., August 15, 2007; 27(16): 5776 - 5789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Williams, P. L. Roulhac, A. G. Roy, R. B. Vallee, M. C. Fitzgerald, and W. A. Hendrickson Structural and thermodynamic characterization of a cytoplasmic dynein light chain intermediate chain complex PNAS, June 12, 2007; 104(24): 10028 - 10033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zakrzewicz, M. Hecker, L. M. Marsh, G. Kwapiszewska, B. Nejman, L. Long, W. Seeger, R. T. Schermuly, N. W. Morrell, R. E. Morty, 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, June 12, 2007; 115(23): 2957 - 2968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Song, G. Benison, A. Nyarko, T. S. Hays, and E. Barbar Potential Role for Phosphorylation in Differential Regulation of the Assembly of Dynein Light Chains J. Biol. Chem., June 8, 2007; 282(23): 17272 - 17279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Sehgal, S. Mukhopadhyay, F. Xu, K. Patel, and M. Shah Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1526 - L1542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tada, S. Majka, M. Carr, J. Harral, D. Crona, T. Kuriyama, and J. West Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1556 - L1563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Meng, A. Lux, A. Holloschi, J. Li, J. M. X. Hughes, T. Foerg, J. E. G. McCarthy, A. M. Heagerty, P. Kioschis, M. Hafner, et al. Identification of Tctex2beta, a Novel Dynein Light Chain Family Member That Interacts with Different Transforming Growth Factor-beta Receptors J. Biol. Chem., December 1, 2006; 281(48): 37069 - 37080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lagna, P. H. Nguyen, W. Ni, and A. Hata BMP-dependent activation of caspase-9 and caspase-8 mediates apoptosis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1059 - L1067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ihida-Stansbury, D. M. McKean, K. B. Lane, J. E. Loyd, L. A. Wheeler, N. W. Morrell, and P. L. Jones Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L694 - L702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bobik Transforming Growth Factor-{beta}s and Vascular Disorders Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1712 - 1720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. K. P. Wong, J. A. Knowles, and J. H. Morse Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src: Implication for a Role in Pulmonary Arterial Hypertension Am. J. Respir. Cell Mol. Biol., November 1, 2005; 33(5): 438 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Yu, H. Beppu, N. Kawai, E. Li, and K. D. Bloch Bone Morphogenetic Protein (BMP) Type II Receptor Deletion Reveals BMP Ligand-specific Gain of Signaling in Pulmonary Artery Smooth Muscle Cells J. Biol. Chem., July 1, 2005; 280(26): 24443 - 24450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Williams, H. Xie, and W. A. Hendrickson Crystal Structure of Dynein Light Chain TcTex-1 J. Biol. Chem., June 10, 2005; 280(23): 21981 - 21986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Yang, L. Long, M. Southwood, N. Rudarakanchana, P. D. Upton, T. K. Jeffery, C. Atkinson, H. Chen, R. C. Trembath, and N. W. Morrell Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension Circ. Res., May 27, 2005; 96(10): 1053 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Harrison, R. Berger, S. G. Haworth, R. Tulloh, C. J. Mache, N. W. Morrell, M. A. Aldred, and R. C. Trembath Transforming Growth Factor-{beta} Receptor Mutations and Pulmonary Arterial Hypertension in Childhood Circulation, February 1, 2005; 111(4): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Chattergoon, F. M. D'Souza, W. Deng, H. Chen, A. L. Hyman, P. J. Kadowitz, and J. R. Jeter Jr. Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L202 - L211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rabinovitch The Mouse Through the Looking Glass: A New Door Into the Pathophysiology of Pulmonary Hypertension Circ. Res., April 30, 2004; 94(8): 1001 - 1004. [Full Text] [PDF]
|
|