Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension

Hum Mol Genet. 2003 Dec 15;12(24):3277-86. doi: 10.1093/hmg/ddg365. Epub 2003 Oct 28.

Abstract

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-beta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein Receptors, Type II
  • Dyneins / metabolism*
  • HeLa Cells
  • Humans
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / metabolism
  • Lung / metabolism
  • Lung / ultrastructure
  • Microtubule-Associated Proteins / metabolism*
  • Models, Biological
  • Mutation*
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Plasmids
  • Protein Isoforms
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Two-Hybrid System Techniques
  • t-Complex Genome Region

Substances

  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Protein Isoforms
  • Protein Serine-Threonine Kinases
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II
  • Dyneins