Published ahead of print on July 7, 2005, doi:10.1165/rcmb.2005-0103OC Am. J. Respir. Cell Mol. Biol., Volume 33, Number 5, November 2005, 438-446 A more recent version of this article appeared on November 1, 2005
Submitted on March 14, 2005 BMPR-II C-Terminus Interacts with C-SRC: Implication for a Role in Pulmonary Arterial HypertensionWai K.P. Wong1*,1 Department of Medicine, Columbia University, New York, NY, USA * To whom correspondence should be addressed. E-mail: wpw2001{at}columbia.edu.
Mutations of bone morphogenetic 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-
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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 co-localized within intracellular aggregates when over-expressed in HEK293 cells. Moreover, mutations truncating the C-terminus disrupted their co-localization whereas missense mutation within kinase domain had no effect on their co-localization. Furthermore, BMP ligand stimulation decreased c-Src activating phosphorylation at Tyr418 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.
