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Molecular and Cellular Biology, June 2008, p. 4004-4017, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00157-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of Proteins Associating with Glycosylphosphatidylinositol- Anchored T-Cadherin on the Surface of Vascular Endothelial Cells: Role for Grp78/BiP in T-Cadherin-Dependent Cell Survival{triangledown} ,{dagger}

Maria Philippova,1* Danila Ivanov,1 Manjunath B. Joshi,1 Emmanouil Kyriakakis,1 Katharina Rupp,1 Taras Afonyushkin,2 Valery Bochkov,2 Paul Erne,3 and Therese J. Resink1

Department of Research, Cardiovascular Laboratories, Basel University Hospital, Hebelstrasse 20, CH 4031 Basel, Switzerland,1 Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria,2 Division of Cardiology, Luzern Kantonsspital, CH 6000 Luzern, Switzerland3

Received 30 January 2008/ Returned for modification 9 March 2008/ Accepted 2 April 2008

There is scant knowledge regarding how cell surface lipid-anchored T-cadherin (T-cad) transmits signals through the plasma membrane to its intracellular targets. This study aimed to identify membrane proteins colocalizing with atypical glycosylphosphatidylinositol (GPI)-anchored T-cad on the surface of endothelial cells and to evaluate their role as signaling adaptors for T-cad. Application of coimmunoprecipitation from endothelial cells expressing c-myc-tagged T-cad and high-performance liquid chromatography revealed putative association of T-cad with the following proteins: glucose-related protein GRP78, GABA-A receptor {alpha}1 subunit, integrin β3, and two hypothetical proteins, LOC124245 and FLJ32070. Association of Grp78 and integrin β3 with T-cad on the cell surface was confirmed by surface biotinylation and reciprocal immunoprecipitation and by confocal microscopy. Use of anti-Grp78 blocking antibodies, Grp78 small interfering RNA, and coexpression of constitutively active Akt demonstrated an essential role for surface Grp78 in T-cad-dependent survival signal transduction via Akt in endothelial cells. The findings herein are relevant in the context of both the identification of transmembrane signaling partners for GPI-anchored T-cad as well as the demonstration of a novel mechanism whereby Grp78 can influence endothelial cell survival as a cell surface signaling receptor rather than an intracellular chaperone.

* Corresponding author. Mailing address: Cardiovascular Laboratories, Basel University Hospital, Hebelstrasse 20, CH 4031 Basel, Switzerland. Phone: 41 61 265 2967. Fax: 41 61 265 2350. E-mail: maria.filippova{at}unibas.ch

{triangledown} Published ahead of print on 14 April 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2008, p. 4004-4017, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00157-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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