This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0103OCv1 33/5/438    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wong, W. K. P. Articles by Morse, J. H. Search for Related Content PubMed PubMed Citation Articles by Wong, W. K. P. Articles by Morse, J. H.

Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src

Implication for a Role in Pulmonary Arterial Hypertension

Departments of Medicine and Psychiatry, Columbia University College of Physicians and Surgeons, and the New York State Psychiatric Institute, New York, New York

Correspondence and requests for reprints should be addressed to Wai K. P. Wong, Ph.D., Columbia University/New York State Psychiatric Institute, 1051 Riverside Drive, Unit 28, Room 5917, New York, NY 10032. E-mail: wpw2001{at}columbia.edu

Mutations of bone morphogenetic protein receptor type II (BMPR-II) have been associated with familial and idiopathic pulmonary arterial hypertension (PAH). BMPR-II is a member of the transforming growth factor- receptor superfamily. It consists of extracellular, transmembrane, and kinase domains, and a unique C-terminus with mostly unknown function. However, a number of PAH-causing mutations are predicted to truncate the C-terminus, suggesting that this domain plays an important role in the homeostasis of pulmonary vessels. In this study, we sought to elucidate the functional role of this C-terminus by seeking its interacting partners. Using yeast two-hybrid screening, we identified c-Src tyrosine kinase as a binding partner of this C-terminus. In vitro co-immunoprecipitation confirmed their interaction. Mutations truncating the C-terminus disrupted their interaction, while missense mutation within kinase domain reduced their interaction. In addition, BMPR-II and c-Src tyrosine kinase colocalized within intracellular aggregates when overexpressed in HEK293 cells. Moreover, mutations truncating the C-terminus disrupted their colocalization, whereas missense mutation within kinase domain had no effect on their colocalization. Furthermore, BMP ligand stimulation decreased c-Src–activating phosphorylation at Tyrosine 418 in pulmonary smooth muscle cells in both time- and concentration-dependent manners. Mutations that truncated the C-terminus abolished this response. Taken together, these results suggest a model in which proliferative effect of c-Src by vasoactive molecules is balanced by opposing effect of BMP signaling in basal state, and the loss of this balance due to BMPR2 mutations leads to increased c-Src activity and subsequently cell growth.

Key Words: bone morphogenetic protein receptor type II • c-Src tyrosine kinase • pulmonary arterial hypertension

This article has been cited by other articles:

				O. Gautschi, C. G. Tepper, P. R. Purnell, Y. Izumiya, C. P. Evans, T. P. Green, P. Y. Desprez, P. N. Lara, D. R. Gandara, P. C. Mack, et al. Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer Cancer Res., April 1, 2008; 68(7): 2250 - 2258. [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]

				G. A. Knock, Y. Shaifta, V. A. Snetkov, B. Vowles, S. Drndarski, J. P.T. Ward, and P. I. Aaronson Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery Cardiovasc Res, February 1, 2008; 77(3): 570 - 579. [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]

				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]