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J. Biol. Chem., Vol. 281, Issue 48, 37069-37080, December 1, 2006

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Identification of Tctex2, a Novel Dynein Light Chain Family Member That Interacts with Different Transforming Growth Factor- Receptors^*

QingJun Meng¹², Andreas Lux^¶13, Andreas Holloschi^¶, Jian Li, John M. X. Hughes^||, Tassilo Foerg^¶, John E. G. McCarthy^||4, Anthony M. Heagerty, Petra Kioschis^¶, Mathias Hafner^¶, and John M. Garland

From the Cardiovascular Clinical Academic Group, University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom, the University Hospital and ^¶Institute of Molecular Cell Biology, University of Applied Sciences, 68163 Mannheim, Germany, and the ^||Manchester Interdisciplinary Biocentre, Manchester M60 1QD, United Kingdom

Endoglin is a membrane-inserted protein that is preferentially synthesized in angiogenic vascular endothelial and smooth muscle cells. Endoglin associates with members of the transforming growth factor- (TGF-) receptor family and has been identified as the gene involved in hereditary hemorrhagic telangiectasia. Although endoglin is known to affect cell responses to TGF-, its mode of action is largely unknown. We performed yeast two-hybrid screening of a human placental cDNA library and isolated a new endoglin-binding partner, a novel 221-amino acid member of the Tctex1/2 family of cytoplasmic dynein light chains named Tctex2, as the founder of a new Tctex1/2 subfamily. The interaction was localized exclusively to the cytoplasmic domain of endoglin. Reverse transcription-PCR showed expression of Tctex2 in a wide range of tissues, including vascular endothelial and smooth muscle cells, placenta, and testis, as well as in several tumor cell lines. High expression levels were found in human umbilical vein endothelial cells and the large cell lung cancer cell line. Forced expression of Tctex2 had a profound inhibitory effect on TGF- signaling. Additional Tctex2-interacting receptors were identified to be the TGF- type II receptor and most likely beta-glycan, but not ALK5, ALK1, or the bone morphogenetic protein type II receptor. Upon fluorescence tagging, co-localization of Tctex2 and endoglin, as well as Tctex2, endoglin, and the TGF- type II receptor, was observed by different microscopy techniques. Our findings link endoglin for the first time to microtubule-based minus end-directed transport machinery, suggesting that some endoglin functions might be regulated and directed by its interaction with the cytoplasmic dynein light chain Tctex2.

Received for publication, September 6, 2006

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ132441 [GenBank] .

^* This work was supported in part by the British Heart Foundation (to J. M. G.) and the Zentrum für Angewandte Forschung-Biotechnologie Zukunftsoffensive (Baden-Würtemberg, Germany) (to A. L., P. K., and M. H.) and the Fritz-Thyssen Foundation (to A. L., T. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

⁴ Supported by the Biotechnology and Biological Sciences Research Council, the Wellcome Trust, the Wolfson Foundation, and the Royal Society.

² To whom correspondence may be addressed. Tel.: 44-161-275-3928; Fax: 44-161-275-3938; E-mail: qjmeng{at}manchester.ac.uk.

³ To whom correspondence may be addressed. Tel.: 49-621-292-6537; Fax: 49-621--292-6420; E-mail: a.lux{at}hs-mannheim.de.

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