Previous Article | Next Article 
Molecular and Cellular Biology, December 2003, p. 9389-9404, Vol. 23, No. 24
0270-7306/03/$08.00+0 DOI: 10.1128/MCB.23.24.9389-9404.2003
Copyright © 2003, American
Society for
Microbiology. All Rights Reserved.
Caveolin-1 Maintains Activated Akt in Prostate Cancer Cells through Scaffolding Domain Binding Site Interactions with and Inhibition of Serine/Threonine Protein Phosphatases PP1 and PP2A
Likun Li,1 Cheng Hui Ren,1 Salahaldin A. Tahir,1 Chengzhen Ren,1 and Timothy C. Thompson1,2,3*
Scott
Department of Urology,1
Department of Molecular and
Cellular Biology,2
Department of
Radiology, Baylor College of Medicine, Houston,
Texas 770303
Received 17 April 2003/
Returned for modification 4 June 2003/
Accepted 9 September 2003
Previously
it has been reported that caveolin-1 (cav-1) has
antiapoptotic activities in prostate cancer cells and functions
downstream of androgenic stimulation. In this study, we demonstrate
that cav-1 overexpression significantly reduced thapsigargin
(Tg)-stimulated apoptosis. Examination of the
phosphatidylinositol 3-kinase (PI3-K)/Akt signaling cascade revealed
higher activities of PDK1 and Akt but not PI3-K in cav-1-stimulated
cells compared to control cells. We subsequently found that cav-1
interacts with and inhibits serine/threonine protein phosphatases PP1
and PP2A through scaffolding domain binding site interactions. Deletion
of the cav-1 scaffolding domain significantly reduces phosphorylated
Akt and cell viability compared with wild-type cav-1. Analysis of
potential substrates for PP1 and PP2A revealed that cav-1-mediated
inhibition of PP1 and PP2A leads to increased PDK1, Akt, and ERK1/2
activities. We demonstrate that increased Akt activities are largely
responsible for cav-1-mediated cell survival using dominant-negative
Akt mutants and specific inhibitors to MEK1/MEK and show that cav-1
increases the half-life of phosphorylated PDK1 and Akt after inhibition
of PI3-K by LY294002. We further demonstrate that cav-1-stimulated Akt
activities lead to increased phosphorylation of multiple Akt
substrates, including GSK3, FKHR, and MDM2. In addition, overexpression
of cav-1 significantly increases translocation of phosphorylated
androgen receptor to nucleus. Our studies therefore reveal a novel
mechanism of Akt activation in prostate cancer and potentially other
malignancies.
* Corresponding
author. Mailing address: Scott Department of Urology, Baylor College of
Medicine, 6560 Fannin, Suite 2100, Houston, TX 77030. Phone: (713)
799-8718. Fax: (713) 794-7983. E-mail:
timothyt{at}www.urol.bcm.tmc.edu.
Molecular and Cellular Biology, December 2003, p. 9389-9404, Vol. 23, No. 24
0022-538X/03/$08.00+0 DOI: 10.1128/MCB.23.24.9389-9404.2003
Copyright © 2003, American
Society for
Microbiology. All Rights Reserved.
This article has been cited by other articles:
-
Hong, K., Lou, L., Gupta, S., Ribeiro-Neto, F., Altschuler, D. L.
(2008). A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation. J. Biol. Chem.
283: 23129-23138
[Abstract]
[Full Text]
-
Matthews, L., Berry, A., Ohanian, V., Ohanian, J., Garside, H., Ray, D.
(2008). Caveolin Mediates Rapid Glucocorticoid Effects and Couples Glucocorticoid Action to the Antiproliferative Program. Mol. Endocrinol.
22: 1320-1330
[Abstract]
[Full Text]
-
Park, S. E., Jeong, S. H., Yee, S.-B., Kim, T. H., Soung, Y. H., Ha, N. C., Kim, N. D., Park, J.-Y., Bae, H. R., Park, B. S., Lee, H. J., Yoo, Y. H.
(2008). Interactions of acetylcholinesterase with caveolin-1 and subsequently with cytochrome c are required for apoptosome formation. Carcinogenesis
29: 729-737
[Abstract]
[Full Text]
-
Santibanez, J. F., Blanco, F. J., Garrido-Martin, E. M., Sanz-Rodriguez, F., del Pozo, M. A., Bernabeu, C.
(2008). Caveolin-1 interacts and cooperates with the transforming growth factor-{beta} type I receptor ALK1 in endothelial caveolae. Cardiovasc Res
77: 791-799
[Abstract]
[Full Text]
-
Tahir, S. A., Yang, G., Goltsov, A. A., Watanabe, M., Tabata, K.-i., Addai, J., Fattah, E. M. A., Kadmon, D., Thompson, T. C.
(2008). Tumor Cell-Secreted Caveolin-1 Has Proangiogenic Activities in Prostate Cancer. Cancer Res.
68: 731-739
[Abstract]
[Full Text]
-
Farwell, W. R., Scranton, R. E., Lawler, E. V., Lew, R. A., Brophy, M. T., Fiore, L. D., Gaziano, J. M.
(2008). The Association Between Statins and Cancer Incidence in a Veterans Population. JNCI J Natl Cancer Inst
100: 134-139
[Abstract]
[Full Text]
-
Heemers, H. V., Tindall, D. J.
(2007). Androgen Receptor (AR) Coregulators: A Diversity of Functions Converging on and Regulating the AR Transcriptional Complex. Endocr. Rev.
28: 778-808
[Abstract]
[Full Text]
-
Arnold, R. S., He, J., Remo, A., Ritsick, D., Yin-Goen, Q., Lambeth, J. D., Datta, M. W., Young, A. N., Petros, J. A.
(2007). Nox1 Expression Determines Cellular Reactive Oxygen and Modulates c-fos-Induced Growth Factor, Interleukin-8, and Cav-1. Am. J. Pathol.
171: 2021-2032
[Abstract]
[Full Text]
-
Zhang, X., Ling, M.-T., Wang, Q., Lau, C.-K., Leung, S. C. L., Lee, T. K., Cheung, A. L. M., Wong, Y.-C., Wang, X.
(2007). Identification of a Novel Inhibitor of Differentiation-1 (ID-1) Binding Partner, Caveolin-1, and Its Role in Epithelial-Mesenchymal Transition and Resistance to Apoptosis in Prostate Cancer Cells. J. Biol. Chem.
282: 33284-33294
[Abstract]
[Full Text]
-
Basu, S., Ray, N. T., Atkinson, S. J., Broxmeyer, H. E.
(2007). Protein Phosphatase 2A Plays an Important Role in Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12-Mediated Migration and Adhesion of CD34+ Cells. J. Immunol.
179: 3075-3085
[Abstract]
[Full Text]
-
Patel, H. H., Zhang, S., Murray, F., Suda, R. Y. S., Head, B. P., Yokoyama, U., Swaney, J. S., Niesman, I. R., Schermuly, R. T., Pullamsetti, S. S., Thistlethwaite, P. A., Miyanohara, A., Farquhar, M. G., Yuan, J. X.-J., Insel, P. A.
(2007). Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. FASEB J.
21: 2970-2979
[Abstract]
[Full Text]
-
Levine, Y. C., Li, G. K., Michel, T.
(2007). Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells: EVIDENCE FOR AN AMPK -> Rac1 -> Akt -> ENDOTHELIAL NITRIC-OXIDE SYNTHASE PATHWAY. J. Biol. Chem.
282: 20351-20364
[Abstract]
[Full Text]
-
Fox, T. E., Houck, K. L., O'Neill, S. M., Nagarajan, M., Stover, T. C., Pomianowski, P. T., Unal, O., Yun, J. K., Naides, S. J., Kester, M.
(2007). Ceramide Recruits and Activates Protein Kinase C {zeta} (PKC{zeta}) within Structured Membrane Microdomains. J. Biol. Chem.
282: 12450-12457
[Abstract]
[Full Text]
-
Nazarenko, I., Schafer, R., Sers, C.
(2007). Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells. J. Cell Sci.
120: 1393-1404
[Abstract]
[Full Text]
-
Rocher, G., Letourneux, C., Lenormand, P., Porteu, F.
(2007). Inhibition of B56-containing Protein Phosphatase 2As by the Early Response Gene IEX-1 Leads to Control of Akt Activity. J. Biol. Chem.
282: 5468-5477
[Abstract]
[Full Text]
-
Nazarenko, I., Kristiansen, G., Fonfara, S., Guenther, R., Gieseler, C., Kemmner, W., Schafer, R., Petersen, I., Sers, C.
(2006). H-REV107-1 Stimulates Growth in Non-Small Cell Lung Carcinomas via the Activation of Mitogenic Signaling. Am. J. Pathol.
169: 1427-1439
[Abstract]
[Full Text]
-
Lu, X., Kambe, F., Cao, X., Yoshida, T., Ohmori, S., Murakami, K., Kaji, T., Ishii, T., Zadworny, D., Seo, H.
(2006). DHCR24-Knockout Embryonic Fibroblasts Are Susceptible to Serum Withdrawal-Induced Apoptosis Because of Dysfunction of Caveolae and Insulin-Akt-Bad Signaling. Endocrinology
147: 3123-3132
[Abstract]
[Full Text]
-
Li, Y. C., Park, M. J., Ye, S.-K., Kim, C.-W., Kim, Y.-N.
(2006). Elevated Levels of Cholesterol-Rich Lipid Rafts in Cancer Cells Are Correlated with Apoptosis Sensitivity Induced by Cholesterol-Depleting Agents. Am. J. Pathol.
168: 1107-1118
[Abstract]
[Full Text]
-
Tso, C.-L., Freije, W. A., Day, A., Chen, Z., Merriman, B., Perlina, A., Lee, Y., Dia, E. Q., Yoshimoto, K., Mischel, P. S., Liau, L. M., Cloughesy, T. F., Nelson, S. F.
(2006). Distinct Transcription Profiles of Primary and Secondary Glioblastoma Subgroups. Cancer Res.
66: 159-167
[Abstract]
[Full Text]
-
Mimeault, M., Batra, S. K.
(2006). Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies. Carcinogenesis
27: 1-22
[Abstract]
[Full Text]
-
Rennebeck, G., Martelli, M., Kyprianou, N.
(2005). Anoikis and Survival Connections in the Tumor Microenvironment: Is There a Role in Prostate Cancer Metastasis?. Cancer Res.
65: 11230-11235
[Abstract]
[Full Text]
-
Williams, T. M., Hassan, G. S., Li, J., Cohen, A. W., Medina, F., Frank, P. G., Pestell, R. G., Di Vizio, D., Loda, M., Lisanti, M. P.
(2005). Caveolin-1 Promotes Tumor Progression in an Autochthonous Mouse Model of Prostate Cancer: GENETIC ABLATION OF Cav-1 DELAYS ADVANCED PROSTATE TUMOR DEVELOPMENT IN TRAMP MICE. J. Biol. Chem.
280: 25134-25145
[Abstract]
[Full Text]
-
Williams, T. M., Lisanti, M. P.
(2005). Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am. J. Physiol. Cell Physiol.
288: C494-C506
[Abstract]
[Full Text]
-
Gonzalez, E., Nagiel, A., Lin, A. J., Golan, D. E., Michel, T.
(2004). Small Interfering RNA-mediated Down-regulation of Caveolin-1 Differentially Modulates Signaling Pathways in Endothelial Cells. J. Biol. Chem.
279: 40659-40669
[Abstract]
[Full Text]
Copyright © 2003 by the American Society for Microbiology. All rights reserved.