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1.
Biol Chem ; 393(6): 495-503, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22628312

RESUMEN

Cadherin-related protein 24 (CDHR24) is a potential tumor suppressor located apically as well as laterally in polarized cells. Here, the role of CDHR24 in contributing to cell morphology and polarity is examined. CDHR24 was predominantly localized at the nonattached part of nonpolarizing cells while another apically sorted protein, aminopeptidase N, was equally distributed over the plasma membrane. Furthermore, CDHR24 expression induced cell aggregation capacity, indicating direct cell-cell interaction. The transepithelial resistance, however, was elevated in polarized MDCK cells, but not in nonpolarizing CHO cells. Our data propose a model in which CDHR24 is directly involved in cell and tissue morphogenesis.


Asunto(s)
Cadherinas/metabolismo , Comunicación Celular , Polaridad Celular , Animales , Células CHO , Cadherinas/química , Cadherinas/genética , Cricetinae , Cricetulus , Citoplasma/metabolismo , Perros , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humanos , Estructura Terciaria de Proteína , Eliminación de Secuencia
3.
J Biol Chem ; 285(37): 28912-23, 2010 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-20605795

RESUMEN

The increased risk of venous thromboembolism in cancer patients has been attributed to enhanced tissue factor (TF) procoagulant activity (PCA) on the surface of cancer cells. Recent studies have shown that TF PCA can be modulated by GRP78, an endoplasmic reticulum (ER)-resident molecular chaperone. In this study, we investigated the role of cell surface GRP78 in modulating TF PCA in several human cancer cell lines. Although both GRP78 and TF are present on the cell surface of cancer cells, there was no evidence of a stable interaction between recombinant human GRP78 and TF, nor was there any effect of exogenously added recombinant GRP78 on cell surface TF PCA. Treatment of cells with the ER stress-inducing agent thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca(2+) pump that causes Ca(2+) efflux from ER stores, increased cytosolic [Ca(2+)] and induced TF PCA. Consistent with these findings, anti-GRP78 autoantibodies that were isolated from the serum of patients with prostate cancer and bind to a specific N-terminal epitope (Leu(98)-Leu(115)) on cell surface GRP78, caused a dose-dependent increase in cytosolic [Ca(2+)] and enhanced TF PCA. The ability to interfere with cell surface GRP78 binding, block phospholipase C activity, sequester ER Ca(2+), or prevent plasma membrane phosphatidylserine exposure resulted in a significant decrease in the TF PCA induced by anti-GRP78 autoantibodies. Taken together, these findings provide evidence that engagement of the anti-GRP78 autoantibodies with cell surface GRP78 increases TF PCA through a mechanism that involves the release of Ca(2+) from ER stores. Furthermore, blocking GRP78 signaling on the surface of cancer cells attenuates TF PCA and has the potential to reduce the risk of cancer-related venous thromboembolism.


Asunto(s)
Anticuerpos Antineoplásicos/inmunología , Autoanticuerpos/inmunología , Calcio/inmunología , Retículo Endoplásmico/inmunología , Proteínas de Choque Térmico/inmunología , Neoplasias de la Próstata/inmunología , Tromboplastina/inmunología , Tromboembolia Venosa/inmunología , Anticuerpos Antineoplásicos/metabolismo , Anticuerpos Antineoplásicos/farmacología , Autoanticuerpos/metabolismo , Autoanticuerpos/farmacología , Calcio/metabolismo , Línea Celular Tumoral , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico , Inhibidores Enzimáticos/farmacología , Epítopos/inmunología , Epítopos/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Fosfatidilserinas/inmunología , Fosfatidilserinas/metabolismo , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/antagonistas & inhibidores , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/inmunología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Tapsigargina/farmacología , Tromboplastina/metabolismo , Fosfolipasas de Tipo C/inmunología , Fosfolipasas de Tipo C/metabolismo , Tromboembolia Venosa/etiología , Tromboembolia Venosa/metabolismo
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